Nicotine salt with meta-salicylic acid and applications therein

ABSTRACT

The present disclosure relates generally to the field of nicotine delivery. The disclosure teaches a nicotine meta-salicylate. More specifically, the disclosure teaches a condensation nicotine aerosol where nicotine meta-salicylate is vaporized. This disclosure relates to aerosol nicotine delivery devices. The delivery devices can be activated by actuation mechanisms to vaporize thin films comprising a nicotine meta-salicylate. More particularly, this disclosure relates to thin films of nicotine salt with meta salicylic acid for the treatment of nicotine craving and for effecting smoking cessation.

RELATED APPLICATIONS

This application claims priority to and is a Continuation of U.S.application Ser. No. 16/235,675 entitled “Nicotine Salt withMeta-Salicylic Acid and Applications Therein”, filed on Dec. 28, 2018,which application claims priority to and is a Divisional of U.S.application Ser. No. 15/671,129, now U.S. Pat. No. 10,166,224, entitled“Nicotine Salt with Meta-Salicylic Acid and Applications Therein”, filedAug. 7, 2017 which application claims priority to and is a Continuationof U.S. application Ser. No. 14/904,359, filed Jan. 11, 2016, now U.S.Pat. No. 9,724,341 entitled “Nicotine Salt with Meta-Salicylic Acid”,which application claims priority to PCT/US2014/046288, filed Jul. 11,2014. This application claims priority to U.S. provisional applicationSer. Nos. 61/845,333 entitled “Nicotine Salt with Meta-Salicylic Acid,”filed Jul. 11, 2013, Myers and U.S. provisional application Ser. No.62/020,766 entitled “Drug Delivery and Cessation System, Apparatus, andMethod,” filed Jul. 3, 2014. The entire disclosures of which are herebyincorporated by reference. Any disclaimer that may have occurred duringthe prosecution of the above-referenced applications is hereby expresslyrescinded, and reconsideration of all relevant art is respectfullyrequested.

TECHNICAL FIELD

The present disclosure relates generally to the field of nicotinedelivery. The disclosure teaches a nicotine meta-salicylate. Morespecifically, the disclosure teaches a condensation nicotine aerosolwhere nicotine meta-salicylate is vaporized. This disclosure relates toaerosol nicotine delivery devices. The delivery devices can be activatedby actuation mechanisms to vaporize thin films comprising a nicotinemeta-salicylate. More particularly, this disclosure relates to thinfilms of nicotine meta-salicylate for the treatment of nicotine cravingand for effecting smoking cessation. The disclosure also relates tomethods, systems, apparatuses, and computer software for deliveringdosages of a drug to a user, and for drug cessation control, and, moreparticularly to methods, systems, apparatuses, and computer software fordelivering dosages of nicotine to a user, and for nicotine cessationcontrol.

BACKGROUND

Cigarette smoking provides an initial sharp rise in nicotine blood levelas nicotine is absorbed through the lungs of a smoker. In general, ablood level peak produced by cigarettes of between 30-40 ng/mL isattained within 10 minutes of smoking. (Hukkanen et al., Am Soc. PharmExp Therap 2013) The rapid rise in nicotine blood level is postulated tobe responsible for the postsynaptic effects at nicotinic cholinergicreceptors in the central nervous system and at autonomic ganglia whichinduces the symptoms experienced by cigarette smokers, and may also beresponsible for the craving symptoms associated with cessation ofsmoking.

While many nicotine replacement therapies have been developed, none ofthe therapies appear to reproduce the pharmacokinetic profile of thesystemic nicotine blood concentration provided by cigarettes. As aconsequence, conventional nicotine replacement therapies have not provento be particularly effective in enabling persons to quit smoking. Forexample, many commercially available products for nicotine replacementin smoking cessation therapy are intended to provide a stable baselineconcentration of nicotine in the blood. Nicotine chewing gum andtransdermal nicotine patches are two examples of smoking cessationproducts which, while providing blood concentrations of nicotine similarto that provided by cigarettes at times greater than about 30 minutes,do not reproduce the sharp initial rise in blood nicotine concentrationsobtained by smoking cigarettes. Nicotine gum is an ion-exchange resinthat releases nicotine slowly when a patient chews, and the nicotinepresent in the mouth is delivered to the systemic circulation by buccalabsorption. Nicotine patches provide a consistent, steady release rate,which leads to low, stable blood levels of nicotine. Thus, both nicotinegum and transdermal nicotine do not reproduce the pharmacokineticprofile of nicotine blood levels obtained through cigarette smoking, andthus do not satisfy the craving symptoms experienced by many smokerswhen attempting to quit smoking.

Inhalation products which generate nicotine vapor are also ineffectiveas inhaled vapors are predominately absorbed through the tongue, mouthand throat, and are not deposited into the lungs. Smokeless nicotineproducts such as chewing tobacco, oral snuff or tobacco sachets delivernicotine to the buccal mucosa where, as with nicotine gum, the releasednicotine is absorbed only slowly and inefficiently. Nicotine bloodlevels from these products require approximately 30 minutes of use toattain a maximum nicotine blood concentration of approximately 12 ng/mL,which is less than half the peak value obtained from smoking onecigarette. Low nicotine blood levels obtained using a buccal absorptionroute may be due to first pass liver metabolism. Orally administeredformulations and lozenges are also relatively ineffective.

Rapid vaporization of thin films of drugs at temperatures up to 600° C.in less than 500 msec in an air flow can produce drug aerosols havinghigh yield and high purity with minimal degradation of the drug.Condensation drug aerosols can be used for effective pulmonary deliveryof drugs using inhalation medical devices. Devices and methods in whichthin films of drugs deposited on metal substrates are vaporized byelectrically resistive heating have been demonstrated. Chemically-basedheat packages which can include a fuel capable of undergoing anexothermic metal oxidation-reduction reaction within an enclosure canalso be used to produce a rapid thermal impulse capable of vaporizingthin films to produce high purity aerosols, as disclosed, for example inU.S. application Ser. No. 10/850,895 entitled “Self-Contained heatingUnit and Drug-Supply Unit Employing Same” filed May 20, 2004, and U.S.application Ser. No. 10/851,883, entitled “Percussively Ignited orElectrically Ignited Self-Contained Heating Unit and Drug Supply UnitEmploying Same,” filed May 20, 2004, the entirety of both of which areherein incorporated by reference. These devices and methods areappropriate for use with compounds that can be deposited as physicallyand chemically stable solids. Unless vaporized shortly after beingdeposited on the metal surface, liquids can evaporate or migrate fromthe surface. Therefore, while such devices can be used to vaporizeliquids, the use of liquid drugs can impose certain undesirablecomplexity. Nicotine is a liquid at room temperature with a relativelyhigh vapor pressure. Therefore, known devices and methods are notparticularly suited for producing nicotine aerosols using the liquiddrug.

It is postulated that treatment of nicotine craving and smokingcessation can be addressed by treatment regimens and/or therapies thatreproduce the rapid onset of high nicotine blood concentrations achievedduring cigarette smoking. A cigarette smoker typically inhales about 10times over a period of about 5 minutes. Therefore, a nicotine deliverydevice capable of simulating the use profile of cigarette smoking caninclude from 5 to 20 doses of up to about 200 μg each of nicotine, whichcould then be intermittently released upon request by the user.

Thus, there remains a need for a nicotine replacement therapy thatprovides a pharmacokinetic profile similar to that obtained by cigarettesmoking, and thereby directly addresses the craving symptoms associatedwith the cessation of smoking.

SUMMARY OF THE EMBODIMENTS

Accordingly, one aspect of the present disclosure teaches nicotinemeta-salicylate. One aspect of the present disclosure provides acompound comprising a volatile nicotine meta-salicylate compound,wherein the compound is selectively vaporizable when heated.

One aspect of the present disclosure provides a nicotine delivery devicecomprising an electric multidose platform (EMD) as shown in FIG. 13 .

One aspect of the present disclosure provides a nicotine delivery devicecomprising a housing defining an airway, wherein the airway comprises atleast one air inlet and a mouthpiece having at least one air outlet, atleast one heat package disposed within the airway, at least nicotinemeta-salicylate disposed on the at least one heat package, and amechanism configured to actuate the at least one heat package.

One aspect of the present disclosure provides a nicotine delivery devicecomprising a housing defining an airway, wherein the airway comprises atleast one air inlet and a mouthpiece having at least one air outlet, atleast one percussively activated heat package disposed within theairway, at least nicotine meta-salicylate disposed on the at least onepercussively activated heat package, and a mechanism configured toimpact the at least one percussively activated heat package. For purposeof clarity, “percussively activated heat package” herein means a heatpackage that has been configured so that it can be fired or activated bypercussion. An “unactivated heat package” or “non-activated heatpackage” refers herein to a percussively activated heat package in adevice, but one that is not yet positioned in the device so that it canbe directly impacted and fired, although the heat package itself isconfigured to be activated by percussion when so positioned.

One aspect of the present disclosure provides a method of producing anaerosol of nicotine by selectively vaporizing the compound from a thinfilm comprising nicotine meta-salicylate.

One aspect of the present disclosure provides a method of deliveringnicotine to a person comprising providing a nicotine delivery devicecomprising, a housing defining an airway, wherein the airway comprisesat least one air inlet and a mouthpiece having at least one air outlet,at least two or more heat packages disposed within the airway, at leastnicotine meta-salicylate disposed on the heat packages, and a mechanismconfigured to activate heat packages, inhaling through the mouthpiece,and activating the heat package, wherein the activated heat packagevaporizes the at least nicotine meta-salicylate to form an aerosolcomprising the nicotine in the airway which is inhaled by the person.

One aspect of the present disclosure provides a method for treatingnicotine craving and smoking cessation using a nicotine aerosol.

One aspect of the present disclosure provides for tapering of thenicotine dose through behavior modification therapy, utilizingelectronic dose controlling and/or tapering through dose reduction.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of certain embodiments, as claimed.

The present invention relates to methods of manufacture and compositionswhich facilitate the inhalation delivery of nicotine to a patient foruse as either a smoking substitute, an aid to smoking cessation, or, aswill be discussed later, in the treatment of illnesses. One embodimentof the present disclosure is capable of delivering nicotine into apatient's blood in a manner which results in attainment of bloodnicotine concentrations similar to the blood nicotine concentrationsattained through smoking cigarettes to thereby address the physicalcravings for nicotine which a smoker develops. In addition, thenicotine-containing dosage form disclosed provides a patient theopportunity, if desired, for physical manipulation and oral stimulationassociated with repeated insertion and removal of the dosage form intoand out of the patient's mouth to thereby address some of thepsychological cravings which a smoker develops.

It is one object of the present disclosure to provide anicotine-containing dosage form which can be utilized as part of along-term smoking cessation program. Another object is to provide anicotine-containing dosage form which is suitable for use as a smokingsubstitute whenever smoking is not allowed or desired. A further objectof the disclosure is to provide a nicotine aerosol highly free of thetoxins present in cigarettes. A further object of the disclosure is toprovide a nicotine-containing dosage form which can maintain nicotineplasma concentrations within a range which alleviates smoking withdrawalsymptoms. Another object of the present disclosure is to provide anicotine-containing dosage form which can provide nicotine plasmaconcentrations similar to those achieved by smoking a cigarette,including a similar pharmacological profile of nicotine delivery.Additionally, the disclosure teaches a nicotine-containing dosage formwhich addresses some of the psychological needs of an individual whodesires to quit smoking. The disclosure also teaches anicotine-containing dosage form which is easy to use in order to promotepatient compliance. The disclosure further teaches thecessation/diminution of the craving for a cigarette by allowing thepatient to self-titrate the amount of nicotine to overcome the person'sindividual craving.

The disclosure teaches a new nicotine salt, nicotine m-salicylate(nicotine meta-salicylate). It is noted that m-salicylic acid is alsoreferred to as 3-hydroxybenzoic acid. In one aspect, the disclosureteaches a novel composition for delivery of nicotine comprising acondensation aerosol formed by volatilizing a heat stable nicotinemeta-salicylate composition under conditions effective to produce aheated vapor of said nicotine meta-salicyl ate composition andcondensing the heated vapor of the drug composition to form condensationaerosol particles, wherein said condensation aerosol particles arecharacterized by less than 10% nicotine degradation products, whereinthe aerosol MMAD is less than 3 microns and wherein said heat stablenicotine meta-salicylate composition comprises nicotine meta-salicylate.

In some variations, the aerosol comprises at least 50% by weight ofnicotine condensation particles. In other variations the aerosolcomprises at least 90% or 95% by weight of the nicotine condensationparticles. Similarly, in some variations, the aerosol is substantiallyfree of thermal degradation products, and in some variations, thecondensation aerosol has a IVIMAD in the range of 0.1-3 μm. In certainembodiments, the particles have an MMAD of less than 5 microns,preferably less than 3 microns. Preferably, the particles have a massmedian aerodynamic diameter of from 0.2 to 5 microns, or most preferablyfrom 0.2 to 3 microns. Typically, the aerosol comprises atherapeutically effective amount of nicotine and in some variations maycomprise pharmaceutically acceptable excipients. In some variations, thecarrier gas is air. In some variations, other gases or a combination ofvarious gases may be used. In some variations, the percent of nicotinefree base is at least 10%. In some variations, the percent of nicotinefree base in the aerosol is at least 20%. In some variations, thepercent of nicotine free base in the aerosol is at least 30%. In somevariations, the percent of nicotine free base in the aerosol is at least40%. In some variations, the percent of nicotine free base in theaerosol is at least 50%. In some variations, the percent of nicotinefree base in the aerosol is between 1% and 10%. In some variations, thepercent of nicotine free base in the aerosol is between 10% and 20%. Insome variations, the percent of nicotine free base in the aerosol isbetween 20% and 30%. In some variations, the percent of nicotine freebase in the aerosol is between 30% and 40%. In some variations, thepercent of nicotine free base in the aerosol is between 40% and 50%.

In another aspect of the invention, the invention provides compositionsfor inhalation delivery, comprising an aerosol of vaporized nicotinecondensed into particles, characterized by less than 5% drug degradationproducts, and wherein said aerosol has a mass median aerodynamicdiameter between 0.1-3 microns.

In some variations of the aerosol compositions, the carrier gas is anon-propellant, non-organic solvent carrier gas. In some variations ofthe aerosol compositions, the carrier gas is air. In some variations,the aerosol is substantially free of organic solvents and propellants.

In other embodiments, aerosols of nicotine are provided that containless than 5% nicotine degradation products, and a mixture of a carriergas and condensation particles, formed by condensation of a vapor ofnicotine in said carrier gas; wherein the MMAD of the aerosol increasesover time, within the size range of 0.1 to 3 microns as said vapor coolsby contact with the carrier gas.

In some variations, the aerosol comprises at least 50% by weight ofnicotine condensation particles. In other variations the aerosolcomprises at least 90% or 95% by weight of the nicotine condensationparticles. In some variations, the MMAD of the aerosol is less than 2microns and increases over time. In some variations, the carrier gas isair. In some variations, other gases or a combination of various gasesmay be used.

The condensation aerosols of the various embodiments are typicallyformed by preparing a film containing a nicotine meta-salicylatecomposition of a desired thickness on a heat-conductive and impermeablesubstrate and heating said substrate to vaporize said film, and coolingsaid vapor thereby producing aerosol particles containing saidcomposition. Rapid heating in combination with the gas flow helps reducethe amount of decomposition. Thus, a heat source is used that typicallyheats the substrate to a temperature of greater than 200° C., preferablyat least 250° C., more preferably at least 300° C. or 350° C. andproduces substantially complete volatilization of the nicotinemeta-salicylate composition from the substrate within a period of 2seconds, preferably, within 1 second, and more preferably, within 0.5seconds.

Typically, the gas flow rate over the vaporizing compound is betweenabout 1 and 10 L/minute. Further, the gas flow rate over the vaporizingcompound can be between about 2 and 8 L/minute.

The film thickness is such that an aerosol formed by vaporizing thenicotine meta-salicylate by heating the substrate and condensing thevaporized compound contains 10% by weight or less nicotine-degradationproduct. The use of thin films allows a more rapid rate of vaporizationand hence, generally, less thermal nicotine degradation. Typically, thefilm has a thickness between 0.05 and 30 microns. In some variations,the film has a thickness between 0.5 and 25 microns. In some variationsthe film has a thickness of about 21 microns. The selected area of thesubstrate surface expanse is such as to yield an effective dose of thenicotine aerosol.

In a related aspect, the disclosure teaches kits for delivering anicotine condensation aerosol that typically comprises a compositiondevoid of solvents and excipients and comprising a heat stable nicotinemeta-salicylate, and a device for forming and delivering via inhalationa condensation aerosol. The device for forming a drug aerosol typicallycomprises an element configured to heat the composition to form a vapor,an element allowing the vapor to condense to form a condensationaerosol, and an element permitting a user to inhale the condensationaerosol. Typically, the element configured to heat the compositioncomprises a heat-conductive substrate and formed on the substrate istypically a nicotine meta-salicylate composition film containing aneffective dose of nicotine when the nicotine is administered in anaerosol form. A heat source in the device is operable to supply heat tothe substrate to produce a substrate temperature, typically that isgreater than 300° C., to substantially volatilize the nicotinemeta-salicylate composition film from the substrate in a period of 2seconds or less, more preferably, in a period of 500 milliseconds orless. The device may further comprise features such as breath-actuation,lockout elements, dose counting/logging or tapering methods.

In yet another aspect, the disclosure teaches kits for deliveringnicotine aerosol comprising a thin film of a nicotine meta-salicylatecomposition and a device for dispensing said film as a condensationaerosol. Typically, the film thickness is between 0.5 and 30 microns.The film can comprise pharmaceutically acceptable excipients and istypically heated at a rate so as to substantially volatilize the film in500 milliseconds or less.

To achieve the foregoing objects, and in accordance with the inventionas embodied and broadly described herein, a nicotine-containing dosageform is provided. The dosage form is configured having anicotine-containing composition wherein the nicotine compositioncomprises nicotine meta-salicylate.

These and other objects and features of the invention will be more fullyappreciated when the following detailed description of the invention isread in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is ortho-salicylic acid, FIG. 1B is para-salicylic acid and FIG.1C is 3-hydroxybenzoic acid (meta-salicylic acid).

FIG. 2 shows a typical calorimetric scan of nicotine m-salicylatepowder.

FIG. 3 shows the ortho isomer.

FIG. 4 shows the para isomer.

FIG. 5 shows the meta isomer.

FIG. 6 is a thermogravimetic analysis plot showing the isothermal massloss of the nicotine meta-salicylate is less than that of nicotineortho-salicylate.

FIG. 7 shows thermogravimetric analysis. Scanning data from roomtemperature to 500° C., showing minimal charring of the acid afterexposure to high temperatures.

FIG. 8 shows a chromatogram of a typical sample run on the nicotineimpurity method.

FIG. 9 shows a chromatogram of a typical sample run on the m-salicylateimpurity method.

FIG. 10 shows the particle size distribution amongst the variousimpactor stages.

FIG. 11 shows particle size distributions.

FIG. 12 shows nicotine mass loss over time.

FIG. 13 shows m-salicylic acid mass loss over time.

FIG. 14 shows unpouched stability summary.

FIG. 15 shows unpouched stability summary.

FIGS. 16A, 16B and 16C are Nicotine device 1.

FIGS. 17A and 17B are Nicotine device 2.

FIGS. 18A and 18B are Nicotine device 3.

FIGS. 19A and 19B are Nicotine device 4.

Reference will now be made in detail to embodiments of the presentdisclosure. While certain embodiments of the present disclosure will bedescribed, it will be understood that it is not intended to limit theembodiments of the present disclosure to those described embodiments. Tothe contrary, reference to embodiments of the present disclosure isintended to cover alternatives, modifications, and equivalents as may beincluded within the spirit and scope of the embodiments of the presentdisclosure as defined by the appended claims.

DESCRIPTION OF VARIOUS EMBODIMENTS Definitions

As defined herein, the following terms shall have the following meaningswhen reference is made to them throughout the specification.

“Aerodynamic diameter” of a given particle refers to the diameter of aspherical droplet with a density of 1 g/mL (the density of water) thathas the same settling velocity as the given particle.

“Aerosol” refers to a collection of solid or liquid particles suspendedin a gas.

“Aerosol mass concentration” refers to the mass of particulate matterper unit volume of aerosol.

“Condensation aerosol” refers to an aerosol that has been formed by thevaporization of a composition and subsequent cooling of the vapor, suchthat the vapor condenses to form particles.

“Decomposition index” refers to a number derived from an assay. Thenumber is determined by subtracting the purity of the generated aerosol,expressed as a fraction, from 1.

“Drug” means any substance that is used in the prevention, diagnosis,alleviation, treatment or cure of a condition. The drug is preferably ina form suitable for thermal vapor delivery, such as an ester, free acid,or free base form. The terms “drug”, “compound”, and “medication” areused herein interchangeably. As described in throughout thespecification, the term drug includes nicotine and nicotinemeta-salicylate.

“Drug composition” refers to a composition that comprises only puredrug, two or more drugs in combination, or one or more drugs incombination with additional components. Additional components caninclude, for example, pharmaceutically acceptable excipients, carriers,and surfactants.

“Drug degradation product” or “thermal degradation product” are usedinterchangeably and means any byproduct, which results from heating thedrug(s) and is not responsible for producing a therapeutic effect.

“Drug supply article” or “drug supply unit” are used interchangeably andrefers to a substrate with at least a portion of its surface coated withone or more drug compositions. Drug supply articles of the invention mayalso include additional elements such as, for example, but notlimitation, a heating element.

“Effective amount of nicotine” means the amount of nicotine required toachieve the effect achieved from nicotine through smoking cigarettes.The effect could be any effect ranging from symptom amelioration withregard to withdraw to symptom treatment. In one embodiment, theeffective amount of nicotine is between 50 to 200 μg/dose.

“Fraction drug degradation product” refers to the quantity of drugdegradation products present in the aerosol particles divided by thequantity of drug plus drug degradation product present in the aerosol,i.e. (sum of quantities of all drug degradation products present in theaerosol)/((quantity of drug(s) present in the aerosol)+(sum ofquantities of all drug degradation products present in the aerosol)).The term “percent drug degradation product” as used herein refers to thefraction drug degradation product multiplied by 100%, whereas “purity”of the aerosol refers to 100% minus the percent drug degradationproducts.

“Heat stable drug” refers to a drug that has a TSR≥9 when vaporized froma film of some thickness between 0.05 μm and 20 μm.

“Mass median aerodynamic diameter” or “MMAD” of an aerosol refers to theaerodynamic diameter for which half the particulate mass of the aerosolis contributed by particles with an aerodynamic diameter larger than theMMAD and half by particles with an aerodynamic diameter smaller than theMMAD.

“Number concentration” refers to the number of particles per unit volumeof aerosol.

“Purity” as used herein, with respect to the aerosol purity, means thefraction of drug composition in the aerosol/the fraction of drugcomposition in the aerosol plus drug degradation products. Thus purityis relative with regard to the purity of the starting material. Forexample, when the starting drug or drug composition used for substratecoating contained detectable impurities, the reported purity of theaerosol does not include those impurities present in the startingmaterial that were also found in the aerosol, e.g., in certain cases ifthe starting material contained a 1% impurity and the aerosol was foundto contain the identical 1% impurity, the aerosol purity maynevertheless be reported as >99% pure, reflecting the fact that thedetectable 1% purity was not produced during thevaporization-condensation aerosol generation process.

“Settling velocity” refers to the terminal velocity of an aerosolparticle undergoing gravitational settling in air.

“Support” refers to a material on which the composition is adhered,typically as a coating or thin film. The term “support” and “substrate”are used herein interchangeably.

“Substantially free of” means that the material, compound, aerosol,etc., being described is at least 95% free of the other component fromwhich it is substantially free.

“Typical patient tidal volume” refers to 1 L for an adult patient and 15mL/kg for a pediatric patient.

“Therapeutically effective amount” means the amount required to achievea therapeutic effect. The therapeutic effect could be any therapeuticeffect ranging from prevention, symptom amelioration, symptom treatment,to disease termination or cure.

“Thermal stability ratio” or “TSR” means the % purity/(100%-% purity) ifthe % purity is <99.9%, and 1000 if the % purity is ≥99.9%. For example,a respiratory drug vaporizing at 90% purity would have a TSR of 9.

“4 μm thermal stability ratio” or “4TSR” means the TSR of a drugdetermined by heating a drug-comprising film of about 4 microns inthickness under conditions sufficient to vaporize at least 50% of thedrug in the film, collecting the resulting aerosol, determining thepurity of the aerosol, and using the purity to compute the TSR. In suchvaporization, generally the about 4-micron thick drug film is heated toaround 350° C. but not less than 200° C. for around 1 second to vaporizeat least 50% of the drug in the film.

“1.5 μm thermal stability ratio” or “1.5TSR” means the TSR of a drugdetermined by heating a drug-comprising film of about 1.5 microns inthickness under conditions sufficient to vaporize at least 50% of thedrug in the film, collecting the resulting aerosol, determining thepurity of the aerosol, and using the purity to compute the TSR. In suchvaporization, generally the about 1.5-micron thick drug film is heatedto around 350° C. but not less than 200° C. for around 1 second tovaporize at least 50% of the drug in the film.

“0.5 μm thermal stability ratio” or “0.5TSR” means the TSR of a drugdetermined by heating a drug-comprising film of about 0.5 microns inthickness under conditions sufficient to vaporize at least 50% of thedrug in the film, collecting the resulting aerosol, determining thepurity of the aerosol, and using the purity to compute the TSR. In suchvaporization, generally the about 0.5-micron thick drug film is heatedto around 350° C. but not less than 200° C. for around 1 second tovaporize at least 50% of the drug in the film.

“Vapor” refers to a gas, and “vapor phase” refers to a gas phase. Theterm “thermal vapor” refers to a vapor phase, aerosol, or mixture ofaerosol-vapor phases, formed preferably by heating.

Nicotine is a heterocyclic compound that can exist in both a free baseand salt forms. The free base form has the following structure:

At 25° C., nicotine is a colorless to pale yellow volatile liquid.Nicotine has a melting point of −79° C., a boiling point at 247° C., anda vapor pressure of 0.0425 mmHg at 25° C. The liquid nature preventsformation of stable films and the high vapor pressure can result inevaporation during shelf-life storage. While various approaches forpreventing nicotine evaporation and degradation during shelf-lifestorage have been considered, for example, delivery from a reservoir viaink jet devices, chemical encapsulation of nicotine as a cyclodextrincomplex, and nicotine containment in blister packs, such implementationshave not been demonstrated to be amendable to low-cost manufacturing,nor easy to reduce to practice in actual devices.

Nicotine Meta-Salicylate

The structure of meta-salicylic acid, also known as 3-hydroxybenzoicacid, is shown in FIG. 2 . This disclosure teaches a nicotine salt withthe meta-salicylic acid. The synthesis of nicotine meta-salicylate isdescribed in Example 1.

The nicotine meta-salicylate has two potentially important advantagesover the commercially available nicotine ortho-salicylate. First,thermogravimetric analysis data show that isothermal mass loss of thenicotine meta-salicylate can be less than that of the nicotineortho-salicylate. For example, at storage temperatures between 40-60°C., nicotine mass loss from nicotine meta-salicylate was about 2-3× lessthan nicotine ortho-salicylate.

Mass loss due to evaporation of the nicotine and/or salicylic acid isdetrimental in view of the product's stability, i.e, the ability toprovide consistent dosing of the drug over the shelf life of theproduct. The meta-salicylate salt is less prone to thermal degradationduring vaporization, particularly with regards to formation of phenol.This is another distinct advantage of the present disclosure. Theposition of the hydroxyl group on the salicylic acid can affect thelikelihood of the decarboxylation of salicylic acid into phenol bycontributing (or not contributing) to resonance stabilization of an ionor free radical. The ortho (and para) isomers have resonance structureswhere the negative charge is localized on the oxygen atom, whereas thisstructure cannot form for the meta isomer. This structure increases thestability of the ion/radical and therefore increases the likelihood orrate of the phenol formation from ortho- or para-salicylic acid.

Aerosol Composition

The compositions described herein typically comprise nicotine compounds.The compositions may comprise other compounds as well. For example, thecomposition may comprise a mixture of drug compounds, a mixture of anicotine compound and a pharmaceutically acceptable excipient, or amixture of a nicotine compound with other compounds having useful ordesirable properties. The composition may comprise a pure nicotinecompound as well. In preferred embodiments, the composition consistsessentially of pure nicotine meta-salicylate and contains no propellantsor solvents.

Additionally, pharmaceutically acceptable carriers, surfactants,enhancers, and inorganic compounds may be included in the composition.Examples of such materials are known in the art.

In some variations, the aerosols are substantially free of organicsolvents and propellants. Additionally, water is typically not added asa solvent for the nicotine meta-salicylate, although water from theatmosphere may be incorporated in the aerosol during formation, inparticular, while passing air over the film and during the coolingprocess. In other variations, the aerosols are completely devoid oforganic solvents and propellants. In yet other variations, the aerosolsare completely devoid of organic solvents, propellants, and anyexcipients. These aerosols comprise only pure drug, less than 10% drugdegradation products, and a carrier gas, which is typically air.

Typically, the drug has a decomposition index less than 0.15.Preferably, the drug has a decomposition index less than 0.10. Morepreferably, the drug has a decomposition index less than 0.05. Mostpreferably, the drug has a decomposition index less than 0.025

In some variations, the condensation aerosol comprises at least 5% byweight of condensation drug aerosol particles. In other variations, theaerosol comprises at least 10%, 20%, 30%, 40%, 50%, 60%, or 75% byweight of condensation drug aerosol particles. In still othervariations, the aerosol comprises at least 95%, 99%, or 99.5% by weightof condensation aerosol particles.

In some variations, the condensation aerosol particles comprise lessthan 10% by weight of a thermal degradation product. In othervariations, the condensation drug aerosol particles comprise less than5%, 1%, 0.5%, 0.1%, or 0.03% by weight of a thermal degradation product.

In certain embodiments of the disclosure, the drug aerosol has a purityof between 90% and 99.8%, or between 93% and 99.7%, or between 95% and99.5%, or between 96.5% and 99.2%. In certain embodiments of thedisclosure, the drug aerosol has percent of freebase nicotine in theaerosol of between 90% and 99.8%, or between 93% and 99.7%, or between95% and 99.5%, or between 96.5% and 99.2%.

Typically, the aerosol has a number concentration greater than 10⁶particles/mL. In other variations, the aerosol has a numberconcentration greater than 10⁷ particles/mL. In yet other variations,the aerosol has a number concentration greater than 10⁸ particles/mL,greater than 10⁹ particles/mL, greater than 10¹⁰ particles/mL, orgreater than 10¹¹ particles/mL.

The gas of the aerosol typically is air. Other gases, however, can beused, in particular inert gases, such as argon, nitrogen, helium, andthe like. The gas can also include vapor of the composition that has notyet condensed to form particles. Typically, the gas does not includepropellants or vaporized organic solvents. In some variations, thecondensation aerosol comprises at least 5% by weight of condensationdrug aerosol particles. In other variations, the aerosol comprises atleast 10%, 20%, 30%, 40%, 50%, 60%, or 75% by weight of condensationdrug aerosol particles. In still other variations, the aerosol comprisesat least 95%, 99%, or 99.5% by weight of condensation aerosol particles.

In some variations the condensation drug aerosol has a MMAD in the rangeof about 0.01-3 μm. In some variations the condensation drug aerosol hasa MMAD in the range of about 0.1-3 μm. In some variations the geometricstandard deviation around the MMAD of the condensation drug aerosolparticles is less than 3.0. In other variations, the geometric standarddeviation around the MMAD of the condensation drug aerosol particles isless than 2.5, or less than 2.0.

In certain embodiments of the invention, the drug aerosol comprises oneor more drugs having a 4TSR of at least 5 or 10, a 1.5TSR of at least 7or 14, or a 0.5TSR of at least 9 or 18. In other embodiments of theinvention, the drug aerosol comprises one or more drugs having a 4TSR ofbetween 5 and 100 or between 10 and 50, a 1.5TSR of between 7 and 200 orbetween 14 and 100, or a 0.5TSR of between 9 and 900 or between 18 and300.

Formation of Condensation Aerosols

Any suitable method may be used to form the condensation aerosolsdescribed herein. One such method involves the heating of a compositionto form a vapor, followed by cooling of the vapor so that it forms anaerosol (i.e., a condensation aerosol). Methods have been previouslydescribed in U.S. Pat. No. 7,090,830. This reference is herebyincorporated by reference in its entirety.

Typically, the composition is coated on a substrate, and then thesubstrate is heated to vaporize the composition. The substrate may be ofany geometry and be of a variety of different sizes. It is oftendesirable that the substrate provide a large surface to volume ratio(e.g., greater than 100 per meter) and a large surface to mass ratio(e.g., greater than 1 cm² per gram). The substrate can have more thanone surface

A substrate of one shape can also be transformed into another shape withdifferent properties. For example, a flat sheet of 0.25 mm thickness hasa surface to volume ratio of approximately 8,000 per meter. Rolling thesheet into a hollow cylinder of 1 cm diameter produces a support thatretains the high surface to mass ratio of the original sheet but has alower surface to volume ratio (about 400 per meter).

A number of different materials may be used to construct the substrate.Typically, the substrates are heat-conductive and include metals, suchas aluminum, iron, copper, stainless steel, and the like, alloys,ceramics, and filled polymers. In one variation, the substrate isstainless steel. Combinations of materials and coated variants ofmaterials may be used as well.

When it is desirable to use aluminum as a substrate, aluminum foil is asuitable material. Examples of alumina and silicon based materialsBCR171 (an alumina of defined surface area greater than 2 m²/g fromAldrich, St. Louis, Mo.) and a silicon wafer as used in thesemiconductor industry.

Typically it is desirable that the substrate have relatively few, orsubstantially no, surface irregularities. Although a variety of supportsmay be used, supports that have an impermeable surface, or animpermeable surface coating, are typically desirable. Illustrativeexamples of such supports include metal foils, smooth metal surfaces,nonporous ceramics, and the like. Alternatively, or in addition, topreferred substrates having an impermeable surface, the substratesurface expanse is characterized by a contiguous surface area of about20 mm². Alternatively, or in addition, to preferred substrates having animpermeable surface, the substrate surface expanse is characterized by acontiguous surface area of greater than 1 mm², preferably 10 mm², morepreferable 50 mm²and still more preferably 100 mm², and a materialdensity of greater than 0.5 g/cc. In contrast, non-preferred substratestypically have a substrate density of less than 0.5 g/cc, such as, forexample, yarn, felts and foam, or have a surface area of less than 1mm²/particle such as, for example small alumina particles, and otherinorganic particles, as it is difficult on these types of surfaces togenerate therapeutic quantities of a drug aerosol with less than 10%drug degradation via vaporization.

In one variation, the disclosure teaches a stainless steel foilsubstrate. A hollow, stainless steel tube may be used as the drug-filmsubstrate. In other variations, aluminum foil is used as a substrate fortesting drug.

The composition is typically coated on the solid support in the form ofa film. The film may be coated on the solid support using any suitablemethod. The method suitable for coating is often dependent upon thephysical properties of the compound and the desired film thickness. Oneexemplary method of coating a composition on a solid support is bypreparing a solution of compound (alone or in combination with otherdesirable compounds) in a suitable solvent, applying the solution to theexterior surface of the solid support, and then removing the solvent(e.g., via evaporation, etc.) thereby leaving a film on the supportsurface.

Common solvents include methanol, dichloromethane, methyl ethyl ketone,diethyl ether, acetone, ethanol, isopropyl alcohol, 3:1chloroform:methanol mixture, 1:1 dichloromethane: methyl ethyl ketonemixture, dimethylformamide, and deionized water. In some instances(e.g., when triamterene is used), it is desirable to use a solvent suchas formic acid. Sonication may also be used as necessary to dissolve thecompound.

The composition may also be coated on the solid support by dipping thesupport into a composition solution, or by spraying, brushing orotherwise applying the solution to the support. Alternatively, a melt ofthe drug can be prepared and applied to the support. For drugs that areliquids at room temperature, thickening agents can be mixed with thedrug to permit application of a solid drug film.

The film can be of varying thickness depending on the compound and themaximum amount of thermal degradation desired. In one method, theheating of the composition involves heating a thin film of thecomposition having a thickness between about 0.1 μm-30 μm to form avapor. In yet other variations, the composition has a film thicknessbetween about 0.5 μm-21 μm. Most typically, the film thickness vaporizedis between 0.5 μm-25 μm.

The support on which the film of the composition is coated can be heatedby a variety of means to vaporize the composition. Exemplary methods ofheating include the passage of current through an electrical resistanceelement, absorption of electromagnetic radiation (e.g., microwave orlaser light) and exothermic chemical reactions (e.g., exothermicsolvation, hydration of pyrophoric materials, and oxidation ofcombustible materials). Heating of the substrate by conductive heatingis also suitable. One exemplary heating source is described in U.S.patent application for SELF-CONTAINED HEATING UNIT AND DRUG-SUPPLY UNITEMPLOYING SAME, U.S. Ser. No. 60/472,697 filed May 21, 2003. Thedescription of the exemplary heating source disclosed therein, is herebyincorporated by reference.

Heat sources typically supply heat to the substrate at a rate thatachieves a substrate temperature of at least 200° C., preferably atleast 250° C., or more preferably at least 300° C. or 350° C., andproduces substantially complete volatilization of the drug compositionfrom the substrate within a period of 2 seconds, preferably, within 1second, or more preferably within 0.5 seconds. Suitable heat sourcesinclude resistive heating devices which are supplied current at a ratesufficient to achieve rapid heating, e.g., to a substrate temperature ofat least 200° C., 250° C., 300° C., or 350° C. preferably within 50-500ms, more preferably in the range of 50-200 ms. Heat sources or devicesthat contain a chemically reactive material which undergoes anexothermic reaction upon actuation, e.g., by a spark or heat element,such as flashbulb type heaters of the type described in severalexamples, and the heating source described in the above-cited U.S.patent application for SELF-CONTAINED HEATING UNIT AND DRUG-SUPPLY UNITEMPLOYING SAME, are also suitable. In particular, heat sources thatgenerate heat by exothermic reaction, where the chemical “load” of thesource is consumed in a period of between 50-500 msec or less aregenerally suitable, assuming good thermal coupling between the heatsource and substrate.

When heating the thin film of the composition, to avoid decomposition,it is desirable that the vaporized compound should transition rapidlyfrom the heated surface or surrounding heated gas to a coolerenvironment. This may be accomplished not only by the rapid heating ofthe substrate, but also by the use of a flow of gas across the surfaceof the substrate. While a vaporized compound from a surface maytransition through Brownian motion or diffusion, the temporal durationof this transition may be impacted by the extent of the region ofelevated temperature at the surface, which is established by thevelocity gradient of gases over the surface and the physical shape ofsurface. Typical gas-flow rates used to minimize such decomposition andto generate a desired particle size are in the range of 1-10 L/minute.

The aerosol particles for administration can typically be formed usingany of the describe methods at a rate of greater than 10⁸ inhalableparticles per second. In some variations, the aerosol particles foradministration are formed at a rate of greater than 10⁹ or 10¹⁰inhalable particles per second. Similarly, with respect to aerosolformation (i.e., the mass of aerosolized particulate matter produced bya delivery device per unit time) the aerosol may be formed at a rategreater than 0.25 mg/second, greater than 0.5 mg/second, or greater than1 or 2 mg/second. Further, with respect to aerosol formation, focusingon the drug aerosol formation rate (i.e., the rate of drug compoundreleased in aerosol form by a delivery device per unit time), the drugmay be aerosolized at a rate greater than 0.05 mg drug per second,greater than 0.1 mg drug per second, greater than 0.5 mg drug persecond, or greater than 1 or 2 mg drug per second.

In some variations, the drug condensation aerosols are formed fromcompositions that provide at least 5% by weight of drug condensationaerosol particles. In other variations, the aerosols are formed fromcompositions that provide at least 10%, 20%, 30%, 40%, 50%, 60%, or 75%by weight of drug condensation aerosol particles. In still othervariations, the aerosols are formed from compositions that provide atleast 95%, 99%, or 99.5% by weight of drug condensation aerosolparticles.

In some variations, the drug condensation aerosol particles when formedcomprise less than 10% by weight of a thermal degradation product. Inother variations, the drug condensation aerosol particles when formedcomprise less than 5%, 1%, 0.5%, 0.1%, or 0.03% by weight of a thermaldegradation product.

In some variations the drug condensation aerosols are produced in a gasstream at a rate such that the resultant aerosols have a MMAD in therange of about 0.1-3 μm. In some variations the geometric standarddeviation around the MMAD of the drug condensation aerosol particles isless than 3.0. In other variations, the geometric standard deviationaround the MMAD of the drug condensation aerosol particles is less than2.5, or less than 2.0.

Delivery Devices

The delivery devices described herein for administering a condensationdrug aerosol typically comprise an element for heating the compositionto form a vapor and an element allowing the vapor to cool, therebyforming a condensation aerosol. These aerosols are generally deliveredvia inhalation to lungs of a patient, for local or systemic treatment.Alternatively, however, the condensation aerosols of the invention canbe produced in an air stream, for application of drug-aerosol particlesto a target site. For example, a stream of air carrying drug-aerosolparticles can be applied to treat an acute or chronic skin condition,can be applied during surgery at the incision site, or can be applied toan open wound. The delivery device may be combined with a compositioncomprising a drug in unit dose form for use as a kit.

The devices described herein may additionally contain a variety ofcomponents to facilitate aerosol delivery. For instance, the device mayinclude any component known in the art to control the timing of drugaerosolization relative to inhalation (e.g., breath-actuation).Similarly, the device may include a component to provide feedback topatients on the rate and/or volume of inhalation, or a component toprevent excessive use (i.e., “lockout” feature). The device may furthercomprise features such as dose counting/logging or tapering methods. Inaddition, the device may further include a component to prevent use byunauthorized individuals, and a component to record dosing histories.These components may be used alone, or in combination with othercomponents. Additionally, the devices may contain features to allow forthe tapering off of nicotine dose.

The element that allows cooling may be of any configuration. Forexample, it may be an inert passageway linking the heating means to theinhalation means. Similarly, the element permitting inhalation by a usermay be of any configuration. For example, it may be an exit portal thatforms a connection between the cooling element and the user'srespiratory system.

Typically, the drug supply article is heated to a temperature sufficientto vaporize all or a portion of the film, so that the composition formsa vapor that becomes entrained in a stream of air during inhalation. Asnoted above, heating of the drug supply article may be accomplishedusing, for example, an electrically-resistive wire embedded or insertedinto the substrate and connected to a battery disposed in the housing.The heating can be actuated, for example, with a button on the housingor via breath actuation, as is known in the art.

Another device that may be used to form and deliver the aerosolsdescribed herein is as follows. The device comprises an element forheating a composition to form a vapor, an element allowing the vapor tocool, thereby forming a condensation aerosol, and an element permittinga user to inhale the aerosol. The device also comprises an upperexternal housing member and a lower external housing member that fittogether.

The downstream end of each housing member is gently tapered forinsertion into a user's mouth. The upstream end of the upper and lowerhousing members are slotted (either one or both are slotted), to providefor air intake when a user inhales. The upper and lower housing memberswhen fitted together define a chamber. Positioned within chamber is adrug supply unit.

The solid support may be of any desirable configuration. At least aportion of the surface of the substrate is coated with a compositionfilm. With the case of the thermite-type heating source, the interiorregion of the substrate contains a substance suitable to generate heat.The substance can be a solid chemical fuel, chemical reagents that mixexothermically, electrically resistive wire, etc. A power supply source,if needed for heating, and any necessary valving for the inhalationdevice may be contained in end piece. A power supply source may be apiece that mates with the drug supply unit.

In one variation of the devices used, the device includes a drugcomposition delivery article composed of the substrate, a film of theselected drug composition on the substrate surface, and a heat sourcefor supplying heat to the substrate at a rate effective to heat thesubstrate to a temperature greater than 200° C. or in other embodimentsto a temperature greater than 250° C., 300° C. or 350° C., and toproduce substantially complete volatilization of the drug compositionwithin a period of 2 seconds or less.

Other drug supply articles that may be used in combination with thedevices described herein. Various methods of coatings are known in theart and/or have been described above.

The illustrative heating element shown as an electrical resistive wirethat produces heat when a current flows through it, but as noted above,a number of different heating methods and corresponding devices areacceptable. For example, acceptable heat sources can supply heat to thedrug supply article at rates that rapidly achieve a temperaturesufficient to completely vaporize the composition from the supportsurface. For example, heat sources that achieve a temperature of 200° C.to 500° C. or more within a period of 2 seconds are typical, although itshould be appreciated that the temperature chosen will be dependent uponthe vaporization properties of the composition, but is typically heatedto a temperature of at least about 200° C., preferably of at least about250° C., more preferably at least about 300° C. or 350° C. Heating thesubstrate produces a drug composition vapor that in the presence of theflowing gas generates aerosol particles in the desired size range. Thepresence of the gas flow is generally prior to, simultaneous with, orsubsequent to heating the substrate. In one embodiment, the substrate isheated for a period of less than about 1 second, and more preferably forless than about 500 milliseconds, still more preferably for less thanabout 200 milliseconds. The drug-aerosol particles are inhaled by asubject for delivery to the lung.

The device may also include a gas-flow control valve disposed upstreamof the solid support, for limiting gas-flow rate through thecondensation region. The gas-flow valve may, for example, include aninlet port communicating with the chamber, and a deformable flap adaptedto divert or restrict airflow away from the port increasingly, withincreasing pressure drop across the valve. Similarly, the gas-flow valvemay include an actuation switch. In this variation, the valve movementwould be in response to an air pressure differential across the valve,which for example, could function to close the switch. The gas-flowvalve may also include an orifice designed to limit airflow rate intothe chamber.

The device may also include a bypass valve communicating with thechamber downstream of the unit for offsetting the decrease in airflowproduced by the gas-flow control valve, as the user draws air into thechamber. In this way, the bypass valve could cooperate with thegas-control valve to control the flow through the condensation region ofthe chamber as well as the total amount of air being drawn through thedevice. Thus the total volumetric airflow through the device in thisvariation would be the sum of the volumetric airflow rate through thegas-control valve and the volumetric airflow rate through the bypassvalve.

The gas control valve could, for example, function to limit air drawninto the device to a preselected level, e.g., 15 L/minute. In this way,airflow for producing particles of a desired size may be preselected andproduced. For example, once this selected airflow level is reached,additional air drawn into the device would create a pressure drop acrossthe bypass valve, which in turn would accommodate airflow through thebypass valve into the downstream end of the device adjacent the user'smouth. Thus, the user senses a full breath being drawn in, with the twovalves distributing the total airflow between desired airflow rate andbypass airflow rate.

These valves may be used to control the gas velocity through thecondensation region of the chamber and hence to control the particlesize of the aerosol particles produced. Typically, the faster theairflow, the smaller the particles are. Thus, to achieve smaller orlarger particles, the gas velocity through the condensation region ofthe chamber may be altered by modifying the gas-flow control valve toincrease or decrease the volumetric airflow rate. For example, toproduce condensation particles in the size range of about 1-3.5 μm MMAD,a chamber having substantially smooth-surfaced walls would have aselected gas-flow rate in the range of 1-10 L/minute.

Additionally, as will be appreciated by one of skill in the art,particle size may be altered by modifying the cross-section of thechamber condensation region to increase or decrease linear gas velocityfor a given volumetric flow rate, and/or the presence or absence ofstructures that produce turbulence within the chamber. Thus, for exampleto produce condensation particles in the size range 10-100 nm MMAD, thechamber may provide gas-flow barriers for creating air turbulence withinthe condensation chamber. These barriers are typically placed within afew thousandths of an inch from the substrate surface. Particle size isdiscussed in more detail below.

Drug Composition Film Thickness

Typically, the drug composition film coated on the solid support has athickness of between about 0.05-30 μm, and typically a thickness between0.1-30 μm. More typically, the thickness is between about 0.2-30 μm;even more typically, the thickness is between about 0.5-30 μm, and mosttypically, the thickness is between about 0.5-25 μm. The desirable filmthickness for any given drug composition is typically determined by aniterative process in which the desired yield and purity of thecondensation aerosol composition are selected or known.

For example, if the purity of the particles is less than that which isdesired, or if the percent yield is less than that which is desired, thethickness of the drug film is adjusted to a thickness different from theinitial film thickness. The purity and yield are then determined at theadjusted film thickness, and this process is repeated until the desiredpurity and yield are achieved. After selection of an appropriate filmthickness, the area of substrate required to provide a therapeuticallyeffective dose is determined.

Generally, the film thickness for a given drug composition is such thatdrug-aerosol particles, formed by vaporizing the drug composition byheating the substrate and entraining the vapor in a gas stream, have (i)10% by weight or less drug-degradation product, more preferably 5% byweight or less, most preferably 2.5% by weight or less and (ii) at least50% of the total amount of drug composition contained in the film. Thearea of the substrate on which the drug composition film is formed isselected to achieve an effective human therapeutic dose of the drugaerosol as is described further below.

To determine the thickness of the drug film, one method that can be usedis to determine the area of the substrate and calculate drug filmthickness using the following relationship:

film thickness(cm)=drug mass(g)/[drug density(g/cm³)×substratearea(cm²)]

The drug mass can be determined by weighing the substrate before andafter formation of the drug film or by extracting the drug and measuringthe amount analytically. Drug density can be experimentally determinedby a variety of techniques, known by those of skill in the art or foundin the literature or in reference texts, such as in the CRC. Anassumption of unit density is acceptable if an actual drug density isnot known.

The substrate having a drug film of known thickness was heated to atemperature sufficient to generate a thermal vapor. All or a portion ofthe thermal vapor was recovered and analyzed for presence ofdrug-degradation products, to determine purity of the aerosol particlesin the thermal vapor. There is a clear relationship between filmthickness and aerosol particle purity, whereas the film thicknessdecreases, the purity increases.

In addition to selection of a drug film thickness that provides aerosolparticles containing 10% or less drug-degradation product (i.e., anaerosol particle purity of 90% or more), the film thickness is selectedsuch that at least about 50% of the total amount of drug compositioncontained in the film is vaporized when the substrate is heated to atemperature sufficient to vaporize the film.

To obtain higher purity aerosols one can coat a lesser amount of drug,yielding a thinner film to heat, or alternatively use the same amount ofdrug but a larger surface area. Generally, except for, as discussedabove, extremely thin thickness of drug film, a linear decrease in filmthickness is associated with a linear decrease in impurities.

Thus for the drug composition where the aerosol exhibits an increasinglevel of drug degradation products with increasing film thicknesses,particularly at a thickness of greater than 0.05-30 microns, the filmthickness on the substrate will typically be between 0.05 and 30microns, e.g., the maximum or near-maximum thickness within this rangethat allows formation of a particle aerosol with drug degradation lessthan 5%.

Another approach contemplates generation of drug-aerosol particleshaving a desired level of drug composition purity by forming the thermalvapor under a controlled atmosphere of an inert gas, such as argon,nitrogen, helium, and the like.

Once a desired purity and yield have been achieved or can be estimatedfrom a graph of aerosol purity versus film thickness and thecorresponding film thickness determined, the area of substrate requiredto provide a therapeutically effective dose is determined.

Substrate Area

As noted above, the surface area of the substrate surface area isselected such that it is sufficient to yield a therapeutically effectivedose. The amount of drug to provide a therapeutic dose is generallyknown in the art and is discussed more below. The required dosage andselected film thickness, discussed above, dictate the minimum requiredsubstrate area in accord with the following relationship:

film thickness(cm)×drug density(g/cm³)×substrate area(cm²)=dose(g)

OR

Substrate area(cm²)=dose(g)/[film thickness(cm)×drug density(g/cm³)]

The drug mass can be determined by weighing the substrate before andafter formation of the drug film or by extracting the drug and measuringthe amount analytically. Drug density can be determined experimentallyby a variety of well-known techniques, or may be found in the literatureor in reference texts, such as in the CRC. An assumption of unit densityis acceptable if an actual drug density is not known.

To prepare a drug supply article comprised of a drug film on aheat-conductive substrate that is capable of administering an effectivehuman therapeutic dose, the minimum substrate surface area is determinedusing the relationships described above to determine a substrate areafor a selected film thickness that will yield a therapeutic dose of drugaerosol.

In some variations, the selected substrate surface area is between about0.05-500 cm². In others, the surface area is between about 0.05 and 300cm². In one embodiment, the substrate surface area is between 0.05 and0.5 cm². In one embodiment, substrate surface areas, are between 0.1 and0.2 cm². The actual dose of drug delivered, i.e., the percent yield orpercent emitted, from the drug-supply article will depend on, along withother factors, the percent of drug film that is vaporized upon heatingthe substrate. Thus, for drug films that yield upon heating 100% of thedrug film and aerosol particles that have a 100% drug purity, therelationship between dose, thickness, and area given above correlatesdirectly to the dose provided to the user. As the percent yield and/orparticle purity decrease, adjustments in the substrate area can be madeas needed to provide the desired dose. Also, as one of skill in the artwill recognize, larger substrate areas other than the minimum calculatedarea for a particular film thickness can be used to deliver atherapeutically effective dose of the drug. Moreover as can beappreciated by one of skill in art, the film need not coat the completesurface area if a selected surface area exceeds the minimum required fordelivering a therapeutic dose from a selected film thickness.

Dosage of Drug Containing Aerosols

The dose of a drug delivered in the aerosol refers to a unit dose amountthat is generated by heating of the drug under defined conditions,cooling the ensuing vapor, and delivering the resultant aerosol. A “unitdose amount” is the total amount of drug in a given volume of inhaledaerosol. The unit dose amount may be determined by collecting theaerosol and analyzing its composition as described herein, and comparingthe results of analysis of the aerosol to those of a series of referencestandards containing known amounts of the drug. The amount of drug ordrugs required in the starting composition for delivery as an aerosoldepends on the amount of drug or drugs entering the thermal vapor phasewhen heated (i.e., the dose produced by the starting drug or drugs), thebioavailability of the aerosol drug or drugs, the volume of patientinhalation, and the potency of the aerosol drug or drugs as a functionof plasma drug concentration.

One can determine the appropriate dose of a drug-containing aerosol totreat a particular condition using methods such as animal experimentsand a dose-finding (Phase I/II) clinical trial. These experiments mayalso be used to evaluate possible pulmonary toxicity of the aerosol. Oneanimal experiment involves measuring plasma concentrations of drug in ananimal after its exposure to the aerosol. Mammals such as dogs orprimates are typically used in such studies, since their respiratorysystems are similar to that of a human and they typically provideaccurate extrapolation of test results to humans. Initial dose levelsfor testing in humans are generally less than or equal to the dose inthe mammal model that resulted in plasma drug levels associated with atherapeutic effect in humans. Dose escalation in humans is thenperformed, until either an optimal therapeutic response is obtained or adose-limiting toxicity is encountered. The actual effective amount ofdrug for a particular patient can vary according to the specific drug orcombination thereof being utilized, the particular compositionformulated, the mode of administration and the age, weight, andcondition of the patient and severity of the episode being treated.

Particle Size

Efficient aerosol delivery to the lungs requires that the particles havecertain penetration and settling or diffusional characteristics.Deposition in the deep lungs occurs by gravitational settling andrequires particles to have an effective settling size, defined as massmedian aerodynamic diameter (MMAD), typically between 1-3.5 μm. Forsmaller particles, deposition to the deep lung occurs by a diffusionalprocess that requires having a particle size in the 10-100 nm, typically20-100 nm range. An inhalation drug-delivery device for deep lungdelivery should produce an aerosol having particles in one of these twosize ranges, preferably between about 0.1-3 μm MMAD. Typically, in orderto produce particles having a desired MMAD, gas or air is passed overthe solid support at a certain flow rate.

During the condensation stage the MMAD of the aerosol is increasing overtime. Typically, in variations of the invention, the MMAD increaseswithin the size range of 0.01-3 microns as the vapor condenses as itcools by contact with the carrier gas then further increases as theaerosol particles collide with each other and coagulate into largerparticles. Most typically, the MMAD grows from <0.5 micron to >1 micronin less than 1 second. Thus typically, immediately after condensing intoparticles, the condensation aerosol MMAD doubles at least once persecond, often at least 2, 4, 8, or 20 times per second. In othervariations, the MMAD increases within the size range of 0.1-3 microns.

Typically, the higher the flow rate, the smaller the particles that areformed. Therefore, in order to achieve smaller or larger particles, theflow rate through the condensation region of the delivery device may bealtered. A desired particle size is achieved by mixing a compound in itsvapor-state into a volume of a carrier gas, in a ratio such that thedesired particle size is achieved when the number concentration of themixture reaches approximately 10⁹ particles/mL. The particle growth atthis number concentration is then slow enough to consider the particlesize to be “stable” in the context of a single deep inhalation. This maybe done, for example, by modifying a gas-flow control valve to increaseor decrease the volumetric airflow rate. To illustrate, condensationparticles in the size range 0.1-3 μm MMAD may be produced by selectingthe gas-flow rate over the vaporizing drug to be in a range of 1-10L/minute, preferably in the range of 2-8 L/min.

Additionally, as will be appreciated by one of skill in the art,particle size may also be altered by modifying the cross-section of thechamber condensation region to increase or decrease linear gas velocityfor a given volumetric flow rate. In addition, particle size may also bealtered by the presence or absence of structures that produce turbulencewithin the chamber. Thus, for example to produce condensation particlesin the size range 10-100 nm MMAD, the chamber may provide gas-flowbarriers for creating air turbulence within the condensation chamber.These barriers are typically placed within a few thousandths of an inchfrom the substrate surface.

Analysis of Drug Containing Aerosols

Purity of a drug-containing aerosol may be determined using a number ofdifferent methods. It should be noted that when the term “purity” isused, it refers to the percentage of aerosol minus the percent byproductproduced in its formation. Byproducts for example, are those unwantedproducts produced during vaporization. For example, byproducts includethermal degradation products as well as any unwanted metabolites of theactive compound or compounds. Examples of suitable methods fordetermining aerosol purity are described in Sekine et al., Journal ofForensic Science 32:1271-1280 (1987) and in Martin et al., Journal ofAnalytic Toxicology 13:158-162 (1989).

One suitable method involves the use of a trap. In this method, theaerosol is collected in a trap in order to determine the percent orfraction of byproduct. Any suitable trap may be used. Suitable trapsinclude filters, glass wool, impingers, solvent traps, cold traps, andthe like. Filters are often most desirable. The trap is then typicallyextracted with a solvent, e.g. acetonitrile, and the extract subjectedto analysis by any of a variety of analytical methods known in the art,for example, gas, liquid, and high performance liquid chromatographyparticularly useful.

The gas or liquid chromatography method typically includes a detectorsystem, such as a mass spectrometry detector or an ultravioletabsorption detector. Ideally, the detector system allows determinationof the quantity of the components of the drug composition and of thebyproduct, by weight. This is achieved in practice by measuring thesignal obtained upon analysis of one or more known mass(es) ofcomponents of the drug composition or byproduct (standards) and thencomparing the signal obtained upon analysis of the aerosol to thatobtained upon analysis of the standard(s), an approach well known in theart.

In many cases, the structure of a byproduct may not be known or astandard for it may not be available. In such cases, one may calculatethe weight fraction of the byproduct by assuming it has an identicalresponse coefficient (e.g. for ultraviolet absorption detection,identical extinction coefficient) to the drug component or components inthe drug composition. When conducting such analysis, byproducts presentin less than a very small fraction of the drug compound, e.g. less than0.1% or 0.03% of the drug compound, are typically excluded. Because ofthe frequent necessity to assume an identical response coefficientbetween drug and byproduct in calculating a weight percentage ofbyproduct, it is often more desirable to use an analytical approach inwhich such an assumption has a high probability of validity. In thisrespect, high performance liquid chromatography with detection byabsorption of ultraviolet light at 225 nm is typically desirable. UVabsorption at 250 nm may be used for detection of compounds in caseswhere the compound absorbs more strongly at 250 nm or for other reasonsone skilled in the art would consider detection at 250 nm the mostappropriate means of estimating purity by weight using HPLC analysis. Incertain cases where analysis of the drug by UV are not viable, otheranalytical tools such as GC/MS or LC/MS may be used to determine purity.

It is possible that changing the gas under which vaporization of thecomposition occurs may also impact the purity.

Other Analytical Methods

Particle size distribution of a drug-containing aerosol may bedetermined using any suitable method in the art (e.g., cascadeimpaction). A Next Generation Cascade Impactor (MSP Corporation,Shoreview, Minn.) linked to a vaporization device by an induction port(USP induction port, MSP Corporation, Shoreview, Minn.) is one systemused for cascade impaction studies.

Inhalable aerosol mass density may be determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the mass collected in the chamber.Typically, the aerosol is drawn into the chamber by having a pressuregradient between the device and the chamber, wherein the chamber is atlower pressure than the device. The volume of the chamber shouldapproximate the inhalation volume of an inhaling patient, typicallyabout 2-4 liters.

Inhalable aerosol drug mass density may be determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the amount of active drug compoundcollected in the chamber. Typically, the aerosol is drawn into thechamber by having a pressure gradient between the device and thechamber, wherein the chamber is at lower pressure than the device. Thevolume of the chamber should approximate the inhalation volume of aninhaling patient, typically about 2-4 liters. The amount of active drugcompound collected in the chamber is determined by extracting thechamber, conducting chromatographic analysis of the extract andcomparing the results of the chromatographic analysis to those of astandard containing known amounts of drug.

Inhalable aerosol particle concentration may be determined, for example,by delivering aerosol phase drug into a confined chamber via aninhalation device and measuring the number of particles of given sizecollected in the chamber. The number of particles of a given size may bedirectly measured based on the light-scattering properties of theparticles. Alternatively, the number of particles of a given size may bedetermined by measuring the mass of particles within the given sizerange and calculating the number of particles based on the mass asfollows: Total number of particles=Sum (from size range 1 to size rangeN) of number of particles in each size range. Number of particles in agiven size range=Mass in the size range/Mass of a typical particle inthe size range. Mass of a typical particle in a given sizerange=π*D³*φ/6, where D is a typical particle diameter in the size range(generally, the mean boundary MMADs defining the size range) in microns,φ is the particle density (in g/mL) and mass is given in units ofpicograms (g⁻¹²).

Rate of inhalable aerosol particle formation may be determined, forexample, by delivering aerosol phase drug into a confined chamber via aninhalation device. The delivery is for a set period of time (e.g., 3 s),and the number of particles of a given size collected in the chamber isdetermined as outlined above. The rate of particle formation is equal tothe number of 10 nm to 5 micron particles collected divided by theduration of the collection time.

Rate of aerosol formation may be determined, for example, by deliveringaerosol phase drug into a confined chamber via an inhalation device. Thedelivery is for a set period of time (e.g., 3 s), and the mass ofparticulate matter collected is determined by weighing the confinedchamber before and after the delivery of the particulate matter. Therate of aerosol formation is equal to the increase in mass in thechamber divided by the duration of the collection time. Alternatively,where a change in mass of the delivery device or component thereof canonly occur through release of the aerosol phase particulate matter, themass of particulate matter may be equated with the mass lost from thedevice or component during the delivery of the aerosol. In this case,the rate of aerosol formation is equal to the decrease in mass of thedevice or component during the delivery event divided by the duration ofthe delivery event.

Rate of drug aerosol formation may be determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device over a set period of time (e.g., 3 s). Where theaerosol is a pure drug, the amount of drug collected in the chamber ismeasured as described above. The rate of drug aerosol formation is equalto the amount of drug collected in the chamber divided by the durationof the collection time. Where the drug-containing aerosol comprises apharmaceutically acceptable excipient, multiplying the rate of aerosolformation by the percentage of drug in the aerosol provides the rate ofdrug aerosol formation.

Kits

In an embodiment of the invention, a kit is provided for use by ahealthcare provider, or more preferably a patient. The kit fordelivering a condensation aerosol typically comprises a compositioncomprising a drug, and a device for forming a condensation aerosol. Thecomposition is typically void of solvents and excipients and generallycomprises a heat stable drug. The device for forming a condensationaerosol typically comprises an element configured to heat thecomposition to form a vapor, an element allowing the vapor to condenseto form a condensation aerosol, and an element permitting a user toinhale the condensation aerosol. The device in the kit may furthercomprise features such as breath-actuation or lockout elements or dosecounting/logging or tapering devices. An exemplary kit will provide ahand-held aerosol delivery device and at least one dose.

In another embodiment, kits for delivering a nicotine aerosol comprisinga thin film of nicotine meta-salicylate composition and a device fordispensing said film as a condensation aerosol are provided. Thecomposition may contain pharmaceutical excipients. The device fordispensing said film of a drug composition as an aerosol comprises anelement configured to heat the film to form a vapor, and an elementallowing the vapor to condense to form a condensation aerosol.

In the kits of the invention, the composition is typically coated as athin film, generally at a thickness between about 0.5-30 microns, on asubstrate which is heated by a heat source. Heat sources typicallysupply heat to the substrate at a rate that achieves a substratetemperature of at least 200° C., preferably at least 250° C., or morepreferably at least 300° C. or 350° C., and produces substantiallycomplete volatilization of the drug composition from the substratewithin a period of 2 seconds, preferably, within 1 second, or morepreferably within 0.5 seconds. To prevent drug degradation, it ispreferable that the heat source does not heat the substrate totemperature greater than 600° C. while the drug film is on the substrateto prevent. More preferably, the heat source does not heat the substratein to temperatures in excess of 500° C.

The kit of the invention can be comprised of various combinations ofnicotine and drug delivery devices. In some embodiments the device mayalso be present with another drug. The other drug may be administeredorally or topically. Generally, instructions for use are included in thekits.

In certain embodiments, thin films of nicotine meta-salicylate can beused to provide multiple doses of nicotine provided on a spool or reelof tape. For example, a tape can comprise a plurality of drug supplyunits with each drug supply unit comprising a heat package on which athin film comprising nicotine meta-salicylate is disposed. Each heatpackage can include an initiator composition that can be ignited, forexample, by resistive heating or percussively, and a fuel capable ofproviding a rapid, high temperature heat impulse sufficient toselectively vaporize the nicotine meta-salicylate. Each heat package canbe spaced at intervals along the length of the tape. During use, one ormore heat packages can be positioned within an airway and, while air isflowing through the airway, the heat package can be activated toselectively vaporize nicotine meta-salicylate. The vaporized nicotinecan condense in the air flow to form an aerosol comprising the nicotinewhich can then be inhaled by a user. The tape can comprise a pluralityof thin films that define the regions where the initiator composition,fuel, and thin film comprising nicotine meta-salicylate are disposed.Certain of the multiple layers can further provide unfilled volume forreleased gases to accumulate to minimize pressure buildup. The pluralityof layers can be formed from any material which can provide mechanicalsupport and that will not appreciably chemically degrade at thetemperatures reached by the heat package. In certain embodiments, alayer can comprise a metal or a polymer such as polyimide,fluoropolymer, polyetherimide, polyether ketone, polyether sulfone,polycarbonate, or other high temperature resistance polymers. In certainembodiments, the tape can further comprise an upper and lower layerconfigured to physically and/or environmentally protect the drug. Theupper and/or lower protective layers can comprise, for example, a metalfoil, a polymer, or can comprise a multilayer comprising metal foil andpolymers. In certain embodiments, protective layers can exhibit lowpermeability to oxygen, moisture, and/or corrosive gases. All orportions of a protective layer can be removed prior to use to expose adrug and fuel. The initiator composition and fuel composition cancomprise, for example, any of those disclosed herein. Thin film heatpackages and drug supply units in the form of a tape, disk, or othersubstantially planar structure, can provide a compact and manufacturablemethod for providing a large number of doses of a substance. Providing alarge number of doses at low cost can be particularly useful in certaintherapies, such as for example, in administering nicotine for thetreatment of nicotine craving and/or effecting cessation of smoking.

The disclosure provides techniques for implementing drug delivery anddrug cessation control. A drug delivery system might be provided havinga form factor similar to a cigarette or cigar in the case that the drugis nicotine, nicotine meta-salicylate, or other nicotine related drug.Within the cigarette or cigar-shaped drug delivery device, a coilarrangement, a foil arrangement, or a resistive contact arrangementmight form a circuit path to a current source. Each coil, foil, orresistive contact might be coated with the nicotine-based drug, or mightbe in thermal contact with a substrate coated with the nicotine-baseddrug. A control device might interface wirelessly with the cigarette orcigar-shaped drug delivery device to wirelessly control or managedelivery of the nicotine-based drug and to control cessation in the useof the drug

In certain embodiments, the disclosure teaches a drug delivery and drugcessation system, comprising: a portable control device comprising auser input device, a first wireless transceiver, a second wirelesstransceiver, a processor, a memory device, and a network interfacedevice; a drug delivery device comprising a third wireless transceiver,a dosage control device, a drug payload, and a dosage delivery device;and one or more user sensors each in contact with a portion of a body ofa user, each of the one or more user sensors comprising a fourthwireless transceiver and one or more measurement sensors, the one ormore measurement sensors comprising one or more of an oximeter, a pulsemeasurement sensor, a respiration rate sensor, or a blood pressuresensor. The user input device receives user inputs from the user tocontrol drug delivery to the body of the user and to control drugcessation; the drug payload comprises a reservoir configured to containamounts of a drug sufficient for one or more doses; the processorcommunicates with the drug delivery device via the first and thirdwireless transceivers to send first instructions to the dosage controldevice based on one or more of the user inputs, one or more presetinstructions associated with drug delivery and drug cessation, or one ormore measurement results from the one or more measurement sensors thatare transmitted to the portable control device via the second and fourthwireless transceivers; the dosage control device determines an amount ofthe drug to be prepared for each dose based on the first instructionsfrom the processor, and sends second instructions to the dosage deliverydevice to prepare and deliver the determined amount of the drug fordelivery for each dose; the dosage delivery device delivers the drugfrom the drug payload to the user based on the second instructions fromthe dosage control device; the memory device stores a history of drugdelivery using the system, the history of drug delivery comprising oneor more of the one or more measurement results prior to each dose, drugdosages for each predetermined period, increases in drug dosage,decreases in drug dosage, number of doses for each predetermined period,increases in number of doses for each predetermined period, decreases innumber of doses for each predetermined period, number of user-initiateddrug delivery overrides, types of user-initiated drug deliveryoverrides, or contact information of a physician associated with theuser; and the network interface communicatively couples with a computingdevice of the physician over a network to send the history of drugdelivery to the physician and to receive drug dosage prescriptions fromthe physician.

The disclosure further teaches a drug delivery and drug cessationsystem, comprising: a portable drug delivery device comprising a drugpayload, a dosage delivery device, and a first wireless transceiver; aportable control device comprising a second wireless transceiver, theportable control device being in wireless communication with theportable drug delivery device via the first wireless transceiver and thesecond wireless transceiver; the portable drug delivery device beingconfigured to deliver a drug to a body of a user based on instructionsreceived from the portable control device. The drug delivery device canbe further characterized wherein the portable drug delivery device is avapor-based drug delivery device.

The disclosure further teaches a drug delivery and drug cessationsystem, wherein the portable drug delivery device further comprises abreath actuator and a lockout unit, wherein the breath actuator isconfigured to cause the dosage delivery device to deliver a supplementaldose of the drug from the drug payload, based on a determination thatthe user has inhaled from the portable drug delivery device, and whereinthe lockout unit is configured to prevent the breath actuator fromcausing the dosage delivery device to deliver the supplemental dose ofthe drug during a predetermined period based on a determination that thesupplemental dose would exceed a predetermined maximum dose of the drugfor the predetermined period.

The drug delivery and drug cessation system may be furthercharacterized, wherein the breath actuator is configured to cause thedosage delivery device to deliver the supplemental dose of the drug fromthe drug payload, based on a determination that the user has inhaledfrom the portable drug delivery device, without receiving theinstructions from the portable control device and contrary to any presetdosage schedule.

The drug delivery and drug cessation system may be furthercharacterized, wherein the drug payload comprises one or more foilscoated with the drug, wherein the dosage delivery device comprises aheater configured to heat one of a portion of each foil or an entiresurface of each foil to at least 200 degrees Celsius within less than 2seconds.

The drug delivery and drug cessation system may be further characterizedwherein the heater is configured to heat one of a portion of each foilor an entire surface of each foil to at least 300 degrees Celsius withinless than 0.5 seconds.

The drug delivery and drug cessation system may be furthercharacterized, wherein the drug payload comprises a plurality ofresistive coils connected in series and a plurality of fuses connectedto a ground wire, each fuse separating each coil from a next adjacentcoil in the series, wherein each of the plurality of coils is coatedwith the drug, wherein the dosage delivery device comprises a currentsource configured to heat each coil to at least 200 degrees Celsiuswithin less than 2 seconds, wherein a circuit path is established fromthe current source to the plurality of coils in the series to the groundwire, with each fuse defining a short-circuit path between each coil andthe next adjacent coil in the series, and wherein the current source isfurther configured to send a short current burst to cause an unfailedfuse closest to the current source to fail, thereby allowing the nextadjacent coil in the series to be energized by the current source.

The drug delivery and drug cessation system may be furthercharacterized, wherein the drug payload comprises a thin film structurecomprising a plurality of foils connected in series and a plurality offuses connected to a ground portion of the thin film structure, eachfuse separating each foil from a next adjacent foil in the series,wherein each of the plurality of foils is coated with the drug, whereinthe dosage delivery device comprises a current source configured to heateach foil to at least 200 degrees Celsius within less than 2 seconds,wherein a circuit path is established from the current source to theplurality of foils in the series to the ground wire, with each fusedefining a short-circuit path between each foil and the next adjacentfoil in the series, and wherein the current source is further configuredto send a short current burst to cause an unfailed fuse closest to thecurrent source to fail, thereby allowing the next adjacent foil in theseries to be energized by the current source.

The drug delivery and drug cessation system may be furthercharacterized, wherein the thin film structure has an overall shape ofone of a flat foil wrapped in wedge form, a flat foil wrapped in tubularform, or a planar structure.

The drug delivery and drug cessation system may be furthercharacterized, wherein the portable drug delivery device is atransdermal-based drug delivery device.

The drug delivery and drug cessation system may be furthercharacterized, wherein the drug payload comprises a liquid reservoircontaining the drug in liquid form, wherein the dosage delivery devicecomprises a variable permeability membrane and a membrane actuator, saidvariable permeability membrane configured to change liquid permeabilityso as to deliver varying amounts of the drug from the liquid reservoir,based on control signals from the membrane actuator.

The drug delivery and drug cessation system may be furthercharacterized, wherein the drug payload comprises a plurality of foilsarranged in a first grid comprising a first plurality of rows and afirst plurality of columns, each foil being coated with the drug andeach foil being separated from each other by electrically and thermallynon-conductive material, wherein the dosage delivery device comprises afirst group of switches, a second group of switches, a current sourceelectrically coupled to each of the first group of switches, anelectrical ground path electrically coupled to each of the second groupof switches, a plurality of actuators arranged in a second gridcomprising a second plurality of rows and a second plurality of columns,a first plurality of linear electrical paths, a second plurality oflinear electrical paths, wherein for each column in the second pluralityof columns, a first electrical path is established from one of the firstgroup of switches to each of the plurality of actuators arranged in thesubject column in the second plurality of columns, wherein for each rowin the second plurality of rows, a second electrical path is establishedfrom one of the second group of switches to each of the plurality ofactuators arranged in the subject column in the second plurality ofrows, wherein the plurality of foils arranged in the first grid isaligned with the plurality of actuators arranged in the second grid soas to make direct contact therewith.

The drug delivery and drug cessation system may be furthercharacterized, wherein each of the plurality of actuators includes aresistive element configured to reach a temperature of at least 200degrees Celsius within less than 2 seconds with application of apredetermined amount of current, wherein each of the plurality of foilsarranged in the first grid is individually heated by closing one of thefirst group of switches and closing one of the second group of switches,thereby energizing a subject resistive element electrically coupled toboth the one of the first group of switches and the one of the secondgroup of switches, in turn heating a subject foil of the plurality offoils that is in direct contact with the subject resistive element.

The drug delivery and drug cessation system of may be furthercharacterized, wherein the dosage delivery device further comprises amembrane in physical contact with the body of the user, wherein the drugheated by the subject foil flows as one of a gas or a liquid through themembrane to be absorbed by a skin portion of the body of the user.

The drug delivery and drug cessation system may be furthercharacterized, wherein each switch in the first and second group ofswitches is a transistor.

The disclosure teaches a drug delivery and drug cessation system furthercomprising: one or more user sensors each in contact with a portion ofthe body of the user, each of the one or more user sensors comprising athird wireless transceiver and one or more measurement sensors, the oneor more measurement sensors comprising one or more of an oximeter, apulse measurement sensor, a respiration rate sensor, or a blood pressuresensor, wherein the portable drug delivery device is configured todeliver the drug to the body of the user based on instructions receivedfrom the portable control device and based on measurement resultsreceived from the one or more measurement sensors via the third wirelesstransceiver.

The disclosure teaches a drug delivery and drug cessation system,wherein the portable control device further comprises a memory deviceand a network interface, wherein the memory device is configured tostore a history of drug delivery using the system, the history of drugdelivery comprising one or more of drug dosages for each predeterminedperiod, increases in drug dosage, decreases in drug dosage, number ofdoses for each predetermined period, increases in number of doses foreach predetermined period, decreases in number of doses for eachpredetermined period, number of user-initiated drug delivery overrides,types of user-initiated drug delivery overrides, or contact informationof a healthcare professional associated with the user, wherein thenetwork interface communicatively couples with a computing device of thehealthcare professional over a network to send the history of drugdelivery to the healthcare professional and to receive drug dosageprescriptions from the healthcare professional.

The disclosure teaches a drug delivery and drug cessation method,comprising: providing a drug delivery and drug cessation system,comprising: a portable drug delivery device comprising a drug payload, adosage delivery device, and a first wireless transceiver; and a portablecontrol device comprising a second wireless transceiver, the portablecontrol device being in wireless communication with the portable drugdelivery device via the first wireless transceiver and the secondwireless transceiver; delivering, by the portable drug delivery device,a dose of a drug stored in the drug payload to a body of a user based onfirst instructions received from the portable control device.

The drug delivery and drug cessation method may be furthercharacterized, comprising: receiving, at the portable control device,second instructions comprising at least one of instructions based onuser input, instructions based on preset dosages, or instructions from ahealthcare professional via a computing device of the healthcareprofessional over a network, wherein the first instructions are based onthe second instructions; and receiving, at the portable drug deliverydevice, the first instructions from the portable control device.

The disclosure teaches a drug delivery and drug cessation apparatus,comprising: a processor; and a non-transitory computer readable mediumhaving stored thereon computer software comprising a set of instructionsthat, when executed by the processor, causes the apparatus to performone or more functions, the set of instructions comprising: instructionsto deliver, by a portable drug delivery device comprising a drugpayload, a dosage delivery device, and a first wireless transceiver, adose of a drug stored in the drug payload to a body of a user based onfirst instructions received from a portable control device comprising asecond wireless transceiver, the portable control device being inwireless communication with the portable drug delivery device via thefirst wireless transceiver and the second wireless transceiver.

The drug delivery and drug cessation apparatus may be furthercharacterized, wherein the set of instructions further comprises:instructions to receive a first set of dosage instructions comprising atleast one of dosage instructions based on user input, dosageinstructions based on preset dosages, or dosage instructions from ahealthcare professional via a computing device of the healthcareprofessional over a network; and instructions to receive, at theportable drug delivery device, the first instructions from the portablecontrol device.

Various embodiments of the disclosure could also include permutations ofthe various elements recited in the claims as if each dependent claimwas a multiple dependent claim incorporating the limitations of each ofthe preceding dependent claims as well as the independent claims. Suchpermutations are expressly within the scope of this disclosure.

While the invention has been particularly shown and described withreference to a number of embodiments, it would be understood by thoseskilled in the art that changes in the form and details may be made tothe various embodiments disclosed herein without departing from thespirit and scope of the invention and that the various embodimentsdisclosed herein are not intended to act as limitations on the scope ofthe claims. All references cited herein are incorporated in theirentirety by reference.

EXAMPLES

The following examples are provided for illustrative purposes only andare not intended to limit the scope of the invention.

Example 1

Synthesis of nicotine meta-salicylate: 1.385 g m-salicylic acid (SigmaAldrich) was dissolved in 25 ml of ethanol. 1.62 g nicotine was addeddrop wise at room temperature and mixed well for approx. 30 minutes. Thesolution was rotary evaporated slowly to reduce the volume to about 10ml. Then 5 ml of ethyl acetate was added and stirred for 3-5 minutes.The solution was placed on dry ice for approx. 1.5 hours, which produceda sticky solid material. After evaporation of the solvent, 20 mL ethanolwas added to dissolve the sticky solid and then evaporated. Thisrecrystallization in known in the art for purifying crystals.Crystalline solid remained in the flask. The powder was removed from theflask and dried in a vacuum oven at 40° C. 2.6 grams were recovered(approx. 87% yield). The melting point of the solid was 125° C.

Example 2

Synthesis of nicotine meta-salicylate: Liquid Nicotine (Alfa Aesar, lot#10150504, purity 99%) and m-salicylic acid (3-hydrobenzoic acid, SigmaAldrich, lot #STBB7747, purity 99%) were used to synthesize nicotinem-salicylate at a 1:1 nicotine:acid ratio. The following synthetic routeleads to typical yields of 60-70% and purity 99.7%.

Sample synthesis:

-   -   1. Dissolved 0.03 moles of m-salicylic acid (˜4.16 g) in 65 ml        of ethanol 200 proof, and mixed well for about 20 min.    -   2. Added 0.03 moles of liquid nicotine (˜4.86 g) to above        solution dropwise, mixed for 30-40 min on stir plate with        periodic shaking. Seed crystals of nicotine m-salicylate were        then added and the solution stirred for another 40 min, then        placed on dry ice for about 40 min.    -   3. Filtered and washed nicotine m-salicylate with 100% acetone        and let it air dry for ˜20 min; to homogenize the salt, a mortar        and pestle were used and then the salt was dried in a vacuum        oven at 40° C. for 1 hour.    -   4. Salt was transferred into a scintillation vial and weighed.        6.0 g were recovered (˜67% yield). The salt is a white powder        with melting point of 125° C. Note that in the very first        synthesis of this material (before there were seed crystals to        utilize), after step 2 (dropwise addition of nicotine) the        solution was rotary evaporated slowly to reduce to ˜10 ml        volume. Then 50 ml of ethyl acetate was added, mixed well, and        the solution placed on dry ice. A sticky material resulted,        which was further evaporated. 20 ml of ethanol was added, the        solution placed again on dry ice, at which point crystallization        occurred. The crystals were filtered, washed and dried under        vacuum at 40° C.

Example 3 API Assessment:

The nicotine m-salicylate raw material (API) was characterized with anumber of analytical methods. The results prove that the nicotinem-salicylate as synthesized is highly pure.

A typical calorimetric scan of nicotine m-salicylate powder isillustrated in FIG. 2 . The melting point is 125° C. Thermogravimetricanalysis on the powder was run in both scanning and isothermal modes.FIG. 7 shows the scanning data, from room temperature to 500° C. Notethe flat baseline near (actually, slightly below) 0%, indicating littleto no residue left behind. The pan was weighed before and after on anexternal balance, and the residual was only ˜0.2%. This result suggestsminimal charring of the acid after exposure to high temperatures.Isothermal data were also obtained on the API powder (˜10 mg per run) at40° C., 50° C., and 60° C. for periods of at least 3 days. In all cases,the mass change was essentially a linear decrease with time. A summaryof the data, along with similar data obtained for various other nicotinesalts, is detailed in Table 2. Nicotine meta-salicyl ate (top line) lostabout 2-3× less nicotine than nicotine ortho-salicylate (second line).Most of the nicotine salts tested were less stable (lost more nicotine)than the m-salicylate salt.

TABLE 2 Nicotine mass loss observed during thermogravimetric analysisexperiments on various nicotine salts Nicotine Mass Loss (mcg/day)Species 40° C. 50° C. 60° C. Nicotine m-salicylate 5 19 107 Nicotineo-salicylate 15 48 178 Nicotine bitartrate 1 3 10 Nicotine monofumarate7 39 219 Nicotine bifumarate 12 66 305 Nicotine 4 14 53bidimethylmalonate Nicotine 51 374 2707 monodimethylmalonate

Example 4 Solubility

Solubility limit tests were performed on nicotine m-salicylate in anumber of relevant solvents. Results are compiled in Table 2. Theapproximate saturation limits are in units of mg nicotine equivalent permL of solvent. Note the solubility of nicotine m-salicylate is low inpure acetonitrile (˜10 mg/mL) and acetone (<10 mg/mL). Nicotinem-salicylate is most soluble in solvent systems containing methanol.However, the analytical methods developed for detecting impuritiesrelated to the m-salicylate use 236 nm as the detection wavelength.Methanol has high absorbance in this range and can therefore interferewith the analytes of interest. Acetonitrile, on the other hand, has lowbackground absorbance in this wavelength range and is therefore idealfor use. To counter the poor solubility, extractions use mixtures ofwater and acetonitrile.

TABLE 3 Approximate Solubility Limits of Nicotine m-salicylate inVarious Solvents Saturation point Solvent (mg nicotine/mL) Acetonitrile 9 Ethanol 33 Water 58 50/50 acetonitrile/water 64 80/20 methanol/water118  Acetone <<10   Methanol 103 

Example 5 Nicotine Coating Development

Spray coating is one of the key manufacturing steps for producing thedrug films that lead to condensation aerosols. Spray coating of nicotinem-salicylate was done with solutions of ˜75 mg/mL in methanol. Acetonewas also tried, but the solubility was limited. Typical spray coatingparameters were 1.3 W (Broadband Ultrasonic Generator power), solutionflow rate 10-12 mL/hr, coating table speed 25 mm/s, and air pressure1-1.5 psi. Higher flow rates tend to lead to visibly more heterogeneouscoatings. Intra-array relative standard deviations were often in the2-3% range, though inter-array variability was higher (likely due tooverspray onto neighboring arrays). Crystallization of the coated filmsis preferable, and usually occurs quite readily after manual seeding ofthe spray nozzle.

Coatings were made such that the 200 μg nicotine equivalent dose coversone surface of the foil, in a 9×2 mm area. This is equivalent to a filmthickness of approximately 20 μm. Lower dosages were coated over thesame surface area, for the characterization studies described below.However, as the mechanical stability of the highest dose was found to beacceptable, and the evaporative loss is less for thicker films, thedisclosure teaches coating at the 20 μm thickness. New spray coatingmasks have been made to produce such films, at doses of 25, 50, and 100μg nicotine equivalent.

Example 6 Analytical Method Development

In conjunction with the drug product development of nicotinem-salicylate, a number of analytical methods have been derived to assistwith the quantitative and qualitative (purity) assessment of the API andthe aerosol.

Nicotine quantitative: This isocratic assay uses a Gemini C18, 50×3.0mm, 3 μm column, 0.1% ammonium hydroxide in water/acetonitrile mobilephase with flow rate of 0.6 mL/min and detection at 245 nm. The totalrun time for this method is 3 minutes. This procedure is applicable fordetermining nicotine concentrations in the range of 8 to 200 μg/mL forlow quant and 100 to 600 μg/mL for high quant in nicotine salts. It isnot intended for the measurement of impurities or degradants ofnicotine.

M-salicylic acid quantitative method: This isocratic assay uses a Luna,C18, 3 μm, 75×4.6 mm column, 0.1% trifluoroacetic acid (TFA) inwater/acetonitrile mobile phase with flow rate of 1.0 mL/min anddetection at 248 nm. The total run time for this method is 3.5 minutes.This procedure is applicable for determining m-salicylic acidconcentrations in the range of 20 to 600 μg/mL. It is not intended forthe measurement of impurities or degradants of m-salicylic acid.

Nicotine purity method: This reverse phase HPLC method applies agradient flow with a mobile phase composed of 0.1% (v/v) ammoniumhydroxide in water/acetonitrile at a flow rate of 0.8 mL/min, and uses aGemini RP18, 150×4.6 mm, 3 μm column, and UV detection at 260 nm. Thetotal run time for this method is 20 minutes. This procedure isapplicable for determining nicotine concentrations and the nicotinerelated impurities in a nicotine concentration range of 300 to 500μg/mL. It is for the determination of the total nicotine-relatedimpurities in nicotine m-salicylate.

M-salicylic acid purity method (AARD-020-049): This reverse phase HPLCmethod applies a gradient flow with a mobile phase composed of 0.1%(v/v) trifluoroacetic acid (TFA) in water/acetonitrile at a flow rate of0.8 mL/min, and uses a Gemini C18, 150×3.0 mm, 5 μm column, and UVdetection at 236 nm. The total run time for this method is 20 minutes.This procedure is applicable for determining m-salicylate concentrationsand the m-salicylate related impurities in an m-salicylate concentrationrange of 300 to 500 μg/mL. It is for the determination of the totalm-salicylic acid-related impurities in nicotine m-salicylate.

Example 7 EMD Characterization Emitted Dose and Mass Balance

Emitted Dose and Mass Balance: Due to the volatile nature of nicotine, athorough collection of nicotine particles and vapors proved to beextremely challenging. Many iterations of emitted dose testing wereperformed to find the optimal collection method that enabled 100% massbalance.

Ultimately, a 76 mm diameter glass fiber filter (1.0 μm pore size, typeA/E), housed in the NGI filter holder, was found to provide the optimalrecovery of both nicotine and the m-salicylate. Possibly the nicotinesalicylate salts require a relatively slow face velocity across thefilter for adequate collection. Emitted dose experiments were conductedusing a switch box with external power supply to provide the energy toheat up the foils and vaporize the drug. Up to 3 foils can be fired intoone filter without negatively impacting recovery. (Actuating more foilsinto one filter decreases aerosol recovery, possibly due to thevolatility of free base nicotine from the extra air flow across thecollection filter.) The switch box was set to provide 3.7 volts/4.0 ampsfor 0.5 seconds. Airflow rate was set at 28.3 LPM. The captured drugvapors were then extracted from the filter using up to 10 mL of 50%(v/v) acetonitrile in water and sonicated for 10 minutes. Filter fibersare pelleted out by centrifugation before the analyte is prepared forHPLC analysis.

The average nicotine emitted dose from foils coated with 200 m nicotinewas 99.5% of coated dose (6.8% SD) while the average m-salicylaterecovery was 101.8% compared to coated dose (6.3% SD). Both had minimaldeposition/residual on the foils and airway housing. Additionally, ananalysis of the nicotine to counter-ion molar ratios for both the coateddose and emitted dose results show that the 1:1 relationship isconserved during the vaporization and capture process.

Aerosol Purity

Aerosols were captured with the emitted dose procedure, with extractionscarried out in 50/50 acetonitrile/water. The purity of the aerosol isdictated by both the nicotine and the salicylate entities. The nicotinemoiety appears to vaporize almost completely intact, with minimal(≤0.5%) degradation. Small amounts of myosmine were detected. FIG. 8shows a chromatogram of a typical sample run on the nicotine impuritymethod.

The challenge of a number of the nicotine salts, such as the tartrate,has been the decomposition of the acid. What complicates the situationfurther is the analytical challenge in observing their degradationbyproducts, since these carboxylic acids are small molecules withminimal UV absorption. The m-salicylate, fortunately, has someadvantages in this regard. We were able to develop an HPLC method forscreening degradation of m-salicylate. Minimal degradation products fromm-salicylic acid have been detected (≤0.5%). FIG. 9 shows a chromatogramof a typical sample run on the m-salicylate impurity method.

An additional concern of the m-salicylic acid was the possible formationof phenol. Phenol has been detected as a decomposition product ofnicotine o-salicylate at levels of ˜0.1-0.5%. While phenol is arelatively ubiquitous molecule, there are some reports of genotoxicityand irritation.

Using a sensitive LC method for phenol detection, this method did notobserve phenol in nicotine m-salicylate aerosols. Given the sensitivityof the method, we can estimate a maximum content of about 0.013% phenolin the nicotine m-salicylate aerosols. A complementary approach toevaluating aerosol purity is calculating the mass balance, i.e.,comparing the coated dose amount to the emitted dose plus the residualamounts of nicotine and counterion. Comparing the amounts and ratio ofnicotine and m-salicylic acid in the coated vs. emitted+residual drugshows that unlike the tremendous disparity seen in salts such asnicotine bitartrate, the mass balance of both entities is about 100% andthe ratio in the aerosol is consistent with that of the coated dose.

Aerosol Particle Size Results

Particle size experiments were conducted on the Next Generation Impactor(NGI). Airflow rate was set at 30 LPM. Foil arrays coated with 200 μg ofnicotine equivalent (about 370 g total of nicotine m-salicylate) werevaporized using an EMD dose cartridge switch box at settings similar tothe emitted dose experiments. Four to eleven foils were vaporized intoeach NGI set and cups were assayed with 4 mL of 50% (v/v) acetonitrilein water. Initially, bare NGI cups resulted in low MMAD values, with anaverage of 0.7 μm. Silicone was then sprayed onto the cups to reduce thebounce effects often seen with particle size experiments. Siliconesprayed cups had no effect on MMAD, though mass balance improvedslightly, increasing nicotine recovery from 76% of coated dose for barecups to 89% on silicone cups. The NGI cups were then coated with a thinlayer of 1% (w/v) benzoic acid to reduce bounce and nicotine volatility.An aliquot of the solution was pipetted into each cup, and the cups wereswirled to expedite surface coverage. The presence of benzoic acidincreased the MMAD to 0.9 μm, while nicotine recovery improved to 93% ofcoated dose. FIG. 10 shows the particle size distribution amongst thevarious impactor stages for these setups.

Further experiments to determine effects of benzoic acid coatinguniformity and thickness (by varying number of sprays from a spraybottle) showed minimal difference to the MMAD, with results ranging from0.8 to 1.0 μm. See FIG. 11 . Particle size is about 1 μm, or justslightly less, which should be appropriate for pulmonary deposition. Itis likely that the nicotine m-salicylate aerosols would grow somewhat inthe humid (nearly 100% RH) atmosphere inside the respiratory tract.

Example 8 Stability

The innate volatility of free base nicotine can be greatly altered oncebound to a counterion acid. The stability of nicotine in the resultingsalt form can vary widely, ultimately impacting its desirability forcommercial consideration. Certain packaging configurations can mitigatenicotine loss. Previous experimental results suggested that nicotineloss is halted once the equilibrium vapor pressure of nicotine isreached. Decreasing the equilibrium vapor pressure point is believed tominimize the total nicotine loss. For this study, different packagingconfigurations were tested to investigate the following variables:container material, presence of adjuncts, and total volume of space.Container materials consisted of either glass or multi-laminate foilpouches. Glass is impermeable to vapors. Once the total volume of theglass container is flooded with nicotine vapors and any surfaceadsorption occurs, equilibrium is reached and no additional loss ofnicotine should be observed. Though foil is also impermeable, the innersurface of the pouch is lined with an ethylene acid copolymer thatpromotes vapor absorbency. The copolymer should lead to greater nicotineloss within a pouch than a glass vial of the same total volume.

The presence of adjuncts, such as a drug cartridge housing, is a likelyscenario for the final commercial product. The composition of theadjunct will affect equilibrium vapor pressure point if itpreferentially absorbs vapors. For this study, a polycarbonate adjunctwith a surface area of ˜150 cm² was introduced to the glass vial andpouch scenarios. Finally, the total packaging volume was examined. Thesmaller the available space, the sooner the equilibrium pressure can bereached. Open containers represent the worst case scenario, as theinfinite space means that the equilibrium pressure can never beachieved. To set up the experiment, screening foils were spray coatedwith a 1×2 cm footprint of nicotine m-salicylate to a thickness of ˜11ug nicotine/mm² (equivalent to a coated dose of 200 ug nicotineequivalent on an EMD foil). After a few random screening foils wereassayed for initial time point coated dose, the remaining foils wereplaced in one of the following containers:

-   -   Capped glass vial (˜40 mL volume)    -   Heat-sealed standard pouch (˜133 mm×87 mm)    -   Heat-sealed standard pouch, stored with polycarbonate material        (˜150 cm² surface area)    -   Uncapped glass vial (same vial as first bullet)    -   Binder-clipped (semi-sealed) standard pouch (˜133 mm×87 mm)    -   Capped glass vial, stored with polycarbonate    -   Heat-sealed half pouch (˜69 mm×87 mm)    -   Uncovered Petri dish

The packaged screening foils were stored at either 40° C. (oven) or 25°C. (laboratory cabinet), without relative humidity control. Atpre-determined time points, three foils from each condition were washedwith 5 mL of 50% v/v acetonitrile in water and analyzed on the HPLC fornicotine and m-salicylate content.

The results for the 40° C. samples are presented in FIG. 14 and FIG. 15. Only two conditions exhibit continued loss of nicotine throughoutstorage duration: the open glass vial and the uncovered Petri dish. Allother conditions in which the packaging was sealed demonstrated astabilization of nicotine volatility after an initial loss.

The sealed standard sized pouches containing polycarbonate materialappear to be the worst of the stabilized nicotine conditions (loss of˜20% nicotine content). The spray coated nicotine salt was exposed tothe copolymer layer and the polycarbonate adjunct and the total volumewas twice that of the half sized pouch. All other stabilized nicotineconditions lost ≤10% of its nicotine content.

The Petri dish condition had the most rapid nicotine loss due to itsstorage configuration. The entire surface of the spray coated foil wascontinually exposed to the outside environment. Meanwhile, the foils inthe open glass vials were stored upright in a narrow vial with only asmall diameter of the space exposed to the outside, thereby reducing therate of loss.

The m-salicylic acid appears to be very stable, regardless of packagingconfiguration. The Petri dish condition is the worst case scenario dueto its maximal exposure to the outside environment. However, after fourweeks of storage at 40° C. with minimal humidity, the m-salicylatecontent remained at ˜80% of initial. Otherwise, the stability resultsare in the range of about 100-110% of initial for all otherconfigurations after 16 weeks of storage.

The results for the samples stored at 25° C. are especially promising.Nicotine loss for all conditions up to 18 weeks of storage were within7% of initial, except for the Petri dish condition (13% loss of nicotinecontent at 18 weeks). The m-salicylic acid content was stable for alleight conditions.

Loss of nicotine and m-salicylic acid due to volatility and hygroscopiceffects: Nicotine salts can suffer volatility issues and can also bequite hygroscopic. For instance, nicotine sulfate absorbs water soreadily that it is shipped in aqueous solution. Hygroscopic effects onnicotine m-salicylate were evaluated for 2 doses at two conditions, 22°C./44% RH (ambient condition) and 40° C./75% RH. According to theAntoine equation for water, 40° C./75% RH translates to supersaturatedhumidity at 22° C. Each coated EMD array was placed flat on a Petri dish(without a cover) which was then stored at either 22° C./44% RH or 40°C./75% RH. At each time point, at least 4 random individual foils wereremoved from the array and each foil was extracted with 1.5 ml of 50/50ACN/water for coated dose determination.

Overall nicotine results for the 40-μg/foil and 170-μg/foil conditionsare summarized as follows. See FIG. 14 . For the 40 μg/foil dose, coatedfilms were relatively stable (defined as not more than 20% loss) for upto 4 hours at 60° C./35% RH, 5 days at 35° C./80% RH, and 4 weeks at 22°C./60% RH. For the 170 μg/foil dose, coated films are stable for atleast 8 hours at 60° C./35% RH, 7 days at 35° C./80% RH, 13 days at 25°C./90% RH and 4 weeks at 22° C./60% RH. Stability results demonstratethat across all stability conditions, the thicker coated films (170μg/foil) are significantly more stable than the thinner coated films (40μg/foil). M-salicylic acid results for 40 μg/foil and 170 μg/foil aresummarized as follows. See FIG. 15 . M-salicylic acid seemed to berelatively stable for all conditions except for the 40 μg/foil dose at25° C./90% RH. Fortunately, this issue can be mitigated by increasingthe coated film thickness.

Mechanical Stability

Fragility of the spray coating was tested using two foil arrays coatedwith ˜200 μg of nicotine per foil (˜11 μg nicotine/mm², which is about a21 μm thick film of nicotine m-salicylate). Five foils from each arraywere assayed for pre-drop coated dose. Each foil array was then placedinto a dose cartridge, sealed into a plastic tube, and dropped 3 timesonto the floor from a height of about 1 meter. Five additional foilsfrom each array were assayed for the post-drop coated dose. Theintra-foil array coated dose was found to be 0.1 and 1.4% higher for thepost-drop compared to pre-drop, with an average of ˜0.8%. In thesecircumstances, these differences are insignificant and show that eventhe 200 μg nicotine equivalent coating of nicotine m-salicylate on theEMD foils are mechanically stable.

TABLE 1 Results of Mechanical Stability Test Nicotine M-salicylate DrugFilm coated dose coated dose thickness Test (average ± 1 (average ± 1(μm)* condition standard deviation) standard deviation) 29 Pre-drop 275± 3 247 ± 1 Post-drop 277 ± 3 244 ± 3 37 Pre-drop 347 ± 6 311 ± 0Post-drop 335 ± 6 299 ± 7 *Assuming unit density (1 g/cm³)

In a follow-up study, we studied the effect of thickness on themechanical integrity of the film. In this experiment, three foils froman array were assayed for pre-drop coated dose. Each foil array was thenplaced into a dose cartridge, sealed into a plastic tube, and dropped 5times onto the floor from a height of about 1 meter. Three foils fromeach array were then assayed for the post-drop coated dose. The dataindicate that film thicknesses corresponding to 350 μg nicotine (˜37 μmthick) begin to show signs of fragility—flaking off of the drug. Thedrug was not lost after dropping of films of ˜29 μm thickness.Therefore, for mechanical purposes, nicotine m-salicylate filmthicknesses should not exceed approximately 30 microns.

Example 9 Devices

Device 1: The basic design as shown in FIGS. 16A, 16B and 16C has beentested in the Electric Multi Dose (EMD) platform. Efficient foilpackaging translates to a large number of doses. The foils are readilycoated via spray process.

Device 2: See FIGS. 17A and 17B. The doses are in the forms of smallcoils, wound from a solid, resistive wire such as Ni-Chrome. The coilsare connected in such a way that the coil furthest from the mouthpieceoffers the path of least resistance. The wire diameter is selected suchthat a short current burst will heat up that coil first, andsubsequently blow the fuse connection point (red dot). At that point,the coil is spent and no longer connected to the circuit. On the nextheating cycle, the next coil presents the path of least resistance, soit becomes the next dose. The cycle continues until all the doses areconsumed. Fail-safe design of single dose can be implemented withoutsoftware. Can be a disposable unit. Form factor can be similar to acigarette. Can leverage from wire bonding technology for coilattachment. Can be converted to software control of heating elements.

Device 3: See FIGS. 18A and 18B. The device relies on the same fusingapproach as Device 2 but it employs foils rather than coils wound fromwire. A fail-safe design of single dose can be implemented withoutsoftware. The device may be a disposable unit. The form factor is closeto a cigarette. The is an efficient area layout which translates tohigher number of doses per device. There are only two connection points.Execution of reduced area for fusing is readily accomplished with thefoil. The device can easily be converted to software controlled heatingelements. Flat foils will be readily coated via a spray process.

Device 4: See FIGS. 19A and 19B. This device relies on the same fusingapproach as in Devices 2 and 3. It employs foils that are wrapped in atubular form to allow for a cigarette like form factor.

The description of the present invention has been presented for purposesof illustration and description, but is not intended to be exhaustive orlimiting of the invention to the form disclosed. The scope of thepresent invention is limited only by the scope of the following claims.Many modifications and variations will be apparent to those of ordinaryskill in the art. The embodiment described and shown in the figures waschosen and described in order to best explain the principles of theinvention, the practical application, and to enable others of ordinaryskill in the art to understand the invention for various embodimentswith various modifications as are suited to the particular usecontemplated.

What is claimed is:
 1. A drug delivery and drug cessation system,comprising: a portable drug delivery device comprising a drug payload, adosage delivery device, and a first wireless transceiver; a portablecontrol device comprising a second wireless transceiver, the portablecontrol device being in wireless communication with the portable drugdelivery device via the first wireless transceiver and the secondwireless transceiver; the portable drug delivery device being configuredto deliver a drug to a body of a user based on instructions receivedfrom the portable control device; wherein the portable drug deliverydevice is a vapor-based drug delivery device; wherein the portable drugdelivery device further comprises a breath actuator and a lockout unit,wherein the breath actuator is configured to cause the dosage deliverydevice to deliver a supplemental dose of the drug from the drug payload,based on a determination that the user has inhaled from the portabledrug delivery device, and wherein the lockout unit is configured toprevent the breath actuator from causing the dosage delivery device todeliver the supplemental dose of the drug during a predetermined periodbased on a determination that the supplemental dose would exceed apredetermined maximum dose of the drug for the predetermined period;wherein the breath actuator is configured to cause the dosage deliverydevice to deliver the supplemental dose of the drug from the drugpayload, based on a determination that the user has inhaled from theportable drug delivery device, without receiving the instructions fromthe portable control device and contrary to any preset dosage schedules.2. The drug delivery and drug cessation system of claim 1, wherein thedrug payload comprises one or more foils coated with the drug, whereinthe dosage delivery device comprises a heater configured to heat one ofa portion of each foil or an entire surface of each foil to at least 200degrees Celsius within less than 2 seconds.
 3. The drug delivery anddrug cessation system of claim 1, wherein the heater is configured toheat one of a portion of each foil or an entire surface of each foil toat least 300 degrees Celsius within less than 0.5 seconds.
 4. The drugdelivery and drug cessation system of claim 1, wherein the drug payloadcomprises a plurality of resistive coils connected in series and aplurality of fuses connected to a ground wire, each fuse separating eachcoil from a next adjacent coil in the series, wherein each of theplurality of coils is coated with the drug, wherein the dosage deliverydevice comprises a current source configured to heat each coil to atleast 200 degrees Celsius within less than 2 seconds, wherein a circuitpath is established from the current source to the plurality of coils inthe series to the ground wire, with each fuse defining a short-circuitpath between each coil and the next adjacent coil in the series, andwherein the current source is further configured to send a short currentburst to cause an unfailed fuse closest to the current source to fail,thereby allowing the next adjacent coil in the series to be energized bythe current source.
 5. The drug delivery and drug cessation system ofclaim 1, wherein the drug payload comprises a thin film structurecomprising a plurality of foils connected in series and a plurality offuses connected to a ground portion of the thin film structure, eachfuse separating each foil from a next adjacent foil in the series,wherein each of the plurality of foils is coated with the drug, whereinthe dosage delivery device comprises a current source configured to heateach foil to at least 200 degrees Celsius within less than 2 seconds,wherein a circuit path is established from the current source to theplurality of foils in the series to the ground wire, with each fusedefining a short-circuit path between each foil and the next adjacentfoil in the series, and wherein the current source is further configuredto send a short current burst to cause an unfailed fuse closest to thecurrent source to fail, thereby allowing the next adjacent foil in theseries to be energized by the current source.
 6. The drug delivery anddrug cessation system of claim 5, wherein the thin film structure has anoverall shape of one of a flat foil wrapped in wedge form, a flat foilwrapped in tubular form, or a planar structure.
 7. The drug delivery anddrug cessation system of claim 1, wherein the drug payload comprises aliquid reservoir containing the drug in liquid form, wherein the dosagedelivery device comprises a variable permeability membrane and amembrane actuator, said variable permeability membrane configured tochange liquid permeability so as to deliver varying amounts of the drugfrom the liquid reservoir, based on control signals from the membraneactuator.
 8. The drug delivery and drug cessation system of claim 1,wherein the drug payload comprises a plurality of foils arranged in afirst grid comprising a first plurality of rows and a first plurality ofcolumns, each foil being coated with the drug and each foil beingseparated from each other by electrically and thermally non-conductivematerial, wherein the dosage delivery device comprises a first group ofswitches, a second group of switches, a current source electricallycoupled to each of the first group of switches, an electrical groundpath electrically coupled to each of the second group of switches, aplurality of actuators arranged in a second grid comprising a secondplurality of rows and a second plurality of columns, a first pluralityof linear electrical paths, a second plurality of linear electricalpaths, wherein for each column in the second plurality of columns, afirst electrical path is established from one of the first group ofswitches to each of the plurality of actuators arranged in the subjectcolumn in the second plurality of columns, wherein for each row in thesecond plurality of rows, a second electrical path is established fromone of the second group of switches to each of the plurality ofactuators arranged in the subject column in the second plurality ofrows, wherein the plurality of foils arranged in the first grid isaligned with the plurality of actuators arranged in the second grid soas to make direct contact therewith.
 9. The drug delivery and drugcessation system of claim 8, wherein each of the plurality of actuatorsincludes a resistive element configured to reach a temperature of atleast 200 degrees Celsius within less than 2 seconds with application ofa predetermined amount of current, wherein each of the plurality offoils arranged in the first grid is individually heated by closing oneof the first group of switches and closing one of the second group ofswitches, thereby energizing a subject resistive element electricallycoupled to both the one of the first group of switches and the one ofthe second group of switches, in turn heating a subject foil of theplurality of foils that is in direct contact with the subject resistiveelement.
 10. The drug delivery and drug cessation system of claim 9,wherein the dosage delivery device further comprises a membrane inphysical contact with the body of the user, wherein the drug heated bythe subject foil flows as one of a gas or a liquid through the membraneto be absorbed by a skin portion of the body of the user.
 11. The drugdelivery and drug cessation system of claim 8, wherein each switch inthe first and second group of switches is a transistor.
 12. The drugdelivery and drug cessation system of claim 1, wherein the drugcomprises one of nicotine, nicotine meta-salicylate, or morphine. 13.The drug delivery and drug cessation system of claim 1, furthercomprising: one or more user sensors each adapted to be in contact witha portion of the body of the user, each of the one or more user sensorscomprising a third wireless transceiver and one or more measurementsensors, the one or more measurement sensors comprising one or more ofan oximeter, a pulse measurement sensor, a respiration rate sensor, or ablood pressure sensor, wherein the portable drug delivery device isconfigured to deliver the drug to the body of the user based oninstructions received from the portable control device and based onmeasurement results received from the one or more measurement sensorsvia the third wireless transceiver.
 14. The drug delivery and drugcessation system of claim 1, wherein the portable control device furthercomprises a memory device and a network interface, wherein the memorydevice is configured to store a history of drug delivery using thesystem, the history of drug delivery comprising one or more of drugdosages for predetermined periods, increases in drug dosage, decreasesin drug dosage, number of doses for each predetermined period, increasesin number of doses for each predetermined period, decreases in number ofdoses for each predetermined period, number of user-initiated drugdelivery overrides, types of user-initiated drug delivery overrides, orcontact information of a healthcare professional associated with theuser, wherein the network interface communicatively couples with acomputing device of the healthcare professional over a network to sendthe history of drug delivery to the healthcare professional and toreceive drug dosage prescriptions from the healthcare professional.